Publications by authors named "Chiara Stagnaro"

28 Publications

  • Page 1 of 1

Impact of first wave of SARS-CoV-2 infection in patients with Systemic Lupus Erythematosus: Weighting the risk of infection and flare.

PLoS One 2021 13;16(1):e0245274. Epub 2021 Jan 13.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Introduction: The aim of this study was to investigate the incidence and clinical presentation of SARS-CoV-2 infections in a Systemic Lupus Erythematosus (SLE) cohort; to assess correlations with disease characteristics and rheumatic therapy; and to evaluate the occurrence of treatment discontinuation and its impact on disease activity.

Materials And Methods: SLE patients monitored by a single Italian centre were interviewed between February and July 2020. Patients were considered to be positive for SARS-CoV-2 infections in case of 1) positive nasopharyngeal swab; 2) positive serology associated with COVID19 suggesting symptoms. The following data were also recorded: clinical symptoms, adoption of social distancing measures, disease activity and treatment discontinuation.

Results: 332 patients were enrolled in the study. Six patients (1.8%) tested positive for SARS-CoV-2 infection, with the incidence being significantly higher in the subgroup of patients treated with biological Disease-Modifying Anti-Rheumatic Drugs (p = 0.005), while no difference was observed for other therapies, age at enrollment, disease duration, type of cumulative organ involvement or adoption of social isolation. The course of the disease was mild. Thirty-six patients (11.1%) discontinued at least part of their therapy during this time period, and 27 (8.1%) cases of disease flare were recorded. Correlation between flare and discontinuation of therapy was statistically significant (p<0.001). No significant increase of rate of flare in a subgroup of the same patients during 2020 was observed.

Conclusion: Treatment discontinuation seems to be an important cause of disease flare. Our findings suggest that abrupt drug withdrawal should be avoided or evaluated with caution on the basis of individual infection risk and comorbidities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806138PMC
January 2021

How do systemic lupus erythematosus patients with very-long disease duration present? Analysis of a monocentric cohort.

Lupus 2021 Mar 7;30(3):439-447. Epub 2021 Jan 7.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objective: to describe the disease path and the very long-term outcome in a monocentric cohort of patients with Systemic Lupus Erythematosus (SLE).

Methods: SLE patients with a disease duration of at least 15 years from diagnosis were enrolled. The number of hospitalizations, the disease flares occurred over the disease course and the organ damage accumulation were evaluated at 1, 2, 3, 4, 5, 10 years from diagnosis and at last observation in 2019 as well. Disease state, ongoing therapies and quality of life measures were also assessed at last visit.

Results: 126 Caucasian SLE patients were included in the analysis (95% female, median age 47.5 IQR 41-53, median disease duration 21 IQR19-26). At last visit, the majority of the patients (78.6%) was on LLDAS (remission included), 53.4% were on GC treatment and 35.7% on immunosuppressant. Furthermore, 53.2% had at least one organ damage. The majority of patients (66.7%) presented a relapsing-remitting course, for a total of 158 flares during the disease course (incidence rate: 0.79/patient-year); moreover, 84.9% of the cohort experienced at least one hospital admission, amounting to a total of 328 hospitalizations (incidence rate: 0.85/patient-year). The main reason for admission was disease activity, while the percentage of hospitalizations due to other causes has been growing over the 10 years of follow-up.

Conclusion: after a very long period of disease, most of the patients with SLE are in remission and are not taking GC therapy; however, the risk of incurring in disease flare remains a real problem.
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http://dx.doi.org/10.1177/0961203320984230DOI Listing
March 2021

Articular involvement, steroid treatment and fibromyalgia are the main determinants of patient-physician discordance in systemic lupus erythematosus.

Arthritis Res Ther 2020 10 14;22(1):241. Epub 2020 Oct 14.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, Italy.

Background: Remission or the lowest possible disease activity is the main target in the management of systemic lupus erythematosus (SLE). Anyway, conflicting data are present in the literature regarding the correlation between physician-driven definitions and patient perception of the disease. The objective of this study is to evaluate the relationship between the definition of lupus low disease activity state (LLDAS) and patient's health-related quality of life (HRQoL).

Methods: This is a cross-sectional, monocentric study. Adult SLE patients were included. For each patient, demographics, disease duration, medications, comorbidities, organ damage, active disease manifestations and SELENA-SLEDAI were assessed. Patients have been categorised as follows: LLDAS, remission and active disease. Each patient completed the following patient-reported outcomes (PROs): SF-36, LIT, FACIT-Fatigue and SLAQ. A SLAQ score < 6 (25° percentile of our cohort) was used as the cut-off value to define a low disease activity state according to patient self-evaluation.

Results: We enrolled 259 consecutive SLE patients (mainly female and Caucasian, mean age 45.33 ± 13.14 years, median disease duration 14 years). 80.3% were in LLDAS, of whom 82.2% were in remission; 19.7% were active. No differences emerged for any of the PROs used between the LLDAS and the active group. Considering the LLDAS subgroup, we identified 56 patients with a subjective low disease activity (SLAQ < 6) and we defined them as "concordant"; the remaining 152 patients in LLDAS presented a subjective active disease (SLAQ ≥ 6) and were defined "discordant". Discordant patients presented more frequently ongoing and past joint involvement (p < 0.05) and a diagnosis of fibromyalgia (p < 0.01); furthermore, they were more likely to be on glucocorticoid therapy (p < 0.01). Discordant patients showed a significantly poorer HRQoL, assessed by all PROs (p < 0.0001).

Conclusions: Joint involvement, glucocorticoid therapy and comorbid fibromyalgia resulted to be the most important variables determining the poor concordance between patient and physician perspective on the disease.
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http://dx.doi.org/10.1186/s13075-020-02334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559765PMC
October 2020

Symmetric peripheral polyarthritis developed during SARS-CoV-2 infection.

Lancet Rheumatol 2020 Sep 13;2(9):e518-e519. Epub 2020 Jul 13.

Rheumatology Unit, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy.

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http://dx.doi.org/10.1016/S2665-9913(20)30216-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357970PMC
September 2020

Translation, cultural adaptation and validation of the Italian version of the Brief Index of Lupus Damage: the BILDit.

Lupus 2020 Sep 13;29(10):1198-1205. Epub 2020 Jul 13.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objectives: The Brief Index of Lupus Damage (BILD) is an instrument of self-evaluation of organ damage for systemic lupus erythematosus (SLE) patients. The objectives of this study were the translation, cultural adaptation and validation of the Italian version of the BILD (BILDit).

Methods: The process of translation and cultural adaptation followed published guidelines. The BILDit was pretested in a pilot study with 30 SLE patients in order to evaluate acceptability, reliability, comprehension and feasibility, and then validated in consecutive SLE patients attending our clinic.

Results: A total of 167 SLE patients were enrolled. In the pilot study, the BILDit demonstrated good acceptability, feasibility and comprehensibility and a very high degree of reliability (Cronbach's α = 1). In the validation cohort, the BILDit showed a significant positive correlation with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI; ρ = 0.69;  < 0.001). Analysing the item-by-item correlation between the BILDit and the SDI, a good correlation ( < 0.001) was found for 73.1% of the items. In the multivariate analysis, the BILDit showed a significant positive correlation with age and disease duration ( < 0.01).

Conclusions: The BILDit seems to be an acceptable and reliable instrument for patient self-evaluation of disease damage, with a good correlation with the SDI. It can be considered as a screening tool for the evaluation of organ damage starting from the patient's perceptive.
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http://dx.doi.org/10.1177/0961203320940012DOI Listing
September 2020

Prognostic Value of Lung Ultrasound B-Lines in Systemic Sclerosis.

Chest 2020 10 29;158(4):1515-1525. Epub 2020 Apr 29.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.

Background: A high percentage of systemic sclerosis (SSc) patients experience interstitial lung disease (ILD) during the disease course. Recent data have shown that lung ultrasound (LUS) can assess ILD by the evaluation of B-lines, the sonographic sign of pulmonary interstitial involvement.

Research Question: To establish the prognostic value of B-lines in a large number of patients with SSc.

Study Design And Methods: A total of 396 consecutive patients with SSc, who were enrolled at three Rheumatology Departments, underwent a comprehensive LUS examination on the anterolateral and posterior chest for a total of 58 scanning sites. All available clinical, imaging, and functional data were recorded. Patients were followed after enrolment to establish the prognostic role of LUS.

Results: The median number of B-lines was higher in patients with the diffuse cutaneous subset (44 vs 17 B-lines; P < .0001), topoisomerase I autoantibodies (39 vs 16 B-lines; P < .0001), and the presence of ILD at chest high-resolution CT (45 vs 9 B-lines; P < .0001). At multivariable analysis, the number of posterior B-lines ≥5 was associated with new development or worsening ILD (hazard ratio, 3.378; 95% CI, 1.137-9.994; P = .028), with additional value over topoisomerase I positivity. The prognostic value was further confirmed in the subgroup of patients with known ILD at baseline (hazard ratio, 1.010; 95% CI, 1.003-1.018; P = .008).

Interpretation: Lung ultrasound B-lines are associated with worsening or development of pulmonary deterioration. In the near future, LUS might become part of the diagnostic and prognostic armamentarium in patients with SSc, which would allow a more sustainable and user-friendly approach to this very fragile population.
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http://dx.doi.org/10.1016/j.chest.2020.03.075DOI Listing
October 2020

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

Ann Rheum Dis 2020 05;79(5):618-625

Department of Rheumatology, University Hospital, Zurich, Switzerland

Objectives: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression.

Methods: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52.

Results: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths.

Conclusions: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
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http://dx.doi.org/10.1136/annrheumdis-2019-216823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213318PMC
May 2020

Lymphopenia as a risk factor for neurologic involvement and organ damage accrual in patients with systemic lupus erythematosus: A multi-center observational study.

Semin Arthritis Rheum 2020 12 4;50(6):1387-1393. Epub 2020 Mar 4.

Department of Medical Sciences, Division of Rheumatology, Uppsala University, Uppsala 751 85, Sweden.

Objective: Detailed analysis of hematological manifestations (HM) in systemic lupus erythematosus (SLE) are limited and their clinical impact on disease remain obscure. Here, we aimed to decipher factors associated with different hematological abnormalities in SLE patients and to assess their impact on disease related outcomes.

Methods: A dataset (GIPT) originating from SLE patients of six European tertiary centers was assessed. Six-monthly visits of each patient for at least 2 years were registered. The association between hematologic manifestations (HM; per ACR-1997criteria) and clinical/serologic variables, as well as the impact of HM on disease related outcomes (damage, infection and hemorrhage) were explored. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI2K), the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and events for any infection and hemorrhage were recorded. Results were compared with a cross-sectional, well-characterized SLE dataset from Sweden. Descriptive statistics, the generalized estimating equations (GEE), general linear models (GLM), Cox regression models were applied.

Results: We monitored 1425 longitudinal visits in 286 SLE patients with HM (GIPT dataset: 88% female, 95% Caucasian, 68% dsDNA positive). Thrombocytopenia (regression coefficient [95% confidence interval] 1.86[1.1-3.13]) and neurologic involvement (ACR-8) (2.1[1.10-3.89]) were associated with lymphopenia (<1000/mm); the latter was an independent predictor of organ damage accrual (1.68[1.2-2.62]). These associations were confirmed in an independent dataset of 1348 SLE patients (86% female, 93% Caucasian, 61% dsDNA positive) in Sweden.Severe lymphopenia (<500/mm) and severe thrombocytopenia (<20 K/mm) were associated with increased risk for infection (hazard ratio [95% confidence interval] 2.56[1.23-5.31]) and hemorrhage (4.38[2.10-11.1]), respectively, independent of the effect of other predictors.

Conclusion: Lymphopenia in SLE is independently associated with neurologic involvement and organ damage accrual, and thus, may be considered as a marker of severe/progressive disease.
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http://dx.doi.org/10.1016/j.semarthrit.2020.02.020DOI Listing
December 2020

Comparison of Early vs. Delayed Anakinra Treatment in Patients With Adult Onset Still's Disease and Effect on Clinical and Laboratory Outcomes.

Front Med (Lausanne) 2020 21;7:42. Epub 2020 Feb 21.

Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy.

Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment. One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences ( < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK. No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months ( = 0.19, = 0.14, and = 0.81, respectively) or 12 months ( = 0.37, = 0.23, and = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment ( = 0.06, = 0.19, and = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset ( = 0.01), while no significance was identified at the 6 and 12 month assessments ( = 0.23 and = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs ( < 0.017). Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.
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http://dx.doi.org/10.3389/fmed.2020.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047849PMC
February 2020

Impact of fatigue on health-related quality of life and illness perception in a monocentric cohort of patients with systemic lupus erythematosus.

RMD Open 2020 02;6(1)

Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa, Italy

Background: Fatigue is a very common and debilitating symptom in patients with systemic lupus erythematosus (SLE), even among those with a mild or inactive disease. The objective of this study is to define fatigue determinants and describe the impact of fatigue on health-related quality of life (HRQoL) and illness perception in a monocentric cohort of patients with SLE.

Methods: This is a cross-sectional study. Adult patients with SLE were included. For each patient, demographics, medications, comorbidities, organ damage (Systemic Lupus International Collaborating Clinics Damage Index), active disease manifestations and Systemic Lupus Disease Activity Index scores were collected. It was evaluated if each patient met the definitions of remission and low disease activity. At enrolment, each patient completed the Short Form-36 (SF-36), Functional Assessment Chronic Illness Therapy-Fatigue (FACIT-F), Lupus Impact Tracker (LIT), Systemic Lupus Activity Questionnaire (SLAQ) and Brief Index of Lupus Damage (BILD). The FACIT-F questionnaire was also administered to a group of healthy controls.

Results: 223 patients were included (mean age 44.9±13.2 years, median disease duration 13 years). 18.2% had an active disease, 43.5% met the definition of remission on treatment, and 11.8% had a concomitant fibromyalgia. The median FACIT-F score of our cohort was significantly lower compared with that of healthy controls (40 vs 47; p<0.001). FACIT-F scores were irrespective of age, disease duration, disease activity and damage. FACIT-F score was significantly lower in patients with fibromyalgia (p<0.01). FACIT-F scores demonstrated a significant correlation with all other patient-reported outcomes: SF-36 (r=0.53-0.77), LIT (r=-0.78), SLAQ (r=-0.72) and BILD (r=-0.28).

Conclusions: Fatigue in patients with SLE has a strong negative impact on HRQoL and patient perception of the disease burden. Fatigue seems irrespective of disease activity but significantly influenced by the presence of fibromyalgia.
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http://dx.doi.org/10.1136/rmdopen-2019-001133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046978PMC
February 2020

Framingham, ACC/AHA or QRISK3: which is the best in systemic lupus erythematosus cardiovascular risk estimation?

Clin Exp Rheumatol 2020 Jul-Aug;38(4):602-608. Epub 2019 Oct 28.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Objectives: Our objective was to compare three algorithms for cardiovascular (CV) risk estimation, namely Framingham, ACC/AHA and QRISK3, in a cohort of patients with systemic lupus erythematosus (SLE).

Methods: Consecutive patients with SLE according to the ACR criteria were enrolled. Traditional risk factors, ongoing therapies, comorbidities and SLE-specific evaluations were assessed. In those without previous myocardial infarction or stroke, Framingham, ACC/AHA and QRISK3 algorithms were then used to estimate the individual risk of developing a CV disease over the next 10 years.

Results: Patients eligible for CV risk estimation were 123 out of 135 enrolled. Framingham index reported a median risk score of 4.7% (IQR 9.5-2.2), considering 29 patients (23.6%) at high CV risk. ACC/AHA index showed a median risk score of 1.4% (IQR 4.5-0.7), with 17 patients (13.8%) at high-risk. QRISK3 revealed a median risk score of 6.2% (IQR 12.5-2.8), making it possible to classify 44 patients (35.8%) at high CV risk. The subgroup analysis of subjects older than 40 years confirmed the same number of high-risk patients for both Framingham and ACC/AHA, whereas QRISK3 classified 38 subjects at high CV risk.

Conclusions: QRISK3 classifies a greater number of SLE patients at high-risk of developing CV diseases over the next 10 years in comparison with classic algorithms as Framingham and ACC/AHA. If its predictive accuracy were confirmed by longitudinal data, QRISK3 could become an important tool in the early detection of a considerable part of CV high-risk SLE patients that would be underestimated when applying classic algorithms.
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September 2020

Pregnancy and undifferentiated connective tissue disease: outcome and risk of flare in 100 pregnancies.

Rheumatology (Oxford) 2020 06;59(6):1335-1339

Rheumatology Unit, Department of Clinical and Experimental Medicine, Pisa.

Objective: UCTD is a systemic autoimmune condition that fails to fulfil the criteria for a definite CTD. Given that there are a lack of studies on links between pregnancy and UCTD, the purpose of this study was to evaluate the risk of disease flares or development of CTD in addition to the risk of adverse pregnancy outcomes in patients with UCTD.

Methods: This is a retrospective study using prospectively collected data for 100 pregnancies in 81 incidences of UCTD treated in a single referral centre.

Results: A total of 11 pregnancies (11%) ended in miscarriage in the first trimester and the remaining 89 (89%) ended with a live birth. Thirteen patients (13%) flared during pregnancy or puerperium and three (3%) suffered major flares that led to the development of SLE with renal involvement. Obstetric complications occurred in 26 of the 89 successful pregnancies (29%), including 1 case (1%) of pre-eclampsia; in some cases, a single pregnancy was affected by more than one complication. There was a significant link between disease flare and both anti-dsDNA-positive antibodies at baseline (P < 0.01) and disease activity at the beginning of pregnancy (P < 0.01).

Conclusion: The impact on pregnancy in the study's cohort appears to be less serious in UCTD than in other CTDs. Nevertheless, disease flares and obstetric complications can represent a clinical challenge and clinical and serological disease activity would appear to represent important determinants of pregnancy outcomes. Pre-pregnancy counselling and planning as well as close monitoring during pregnancy is therefore essential.
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http://dx.doi.org/10.1093/rheumatology/kez440DOI Listing
June 2020

Is there a role for laser speckle contrast analysis (LASCA) in predicting the outcome of digital ulcers in patients with systemic sclerosis?

Clin Rheumatol 2020 Jan 17;39(1):69-75. Epub 2019 Jul 17.

Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.

Objective: Digital ulcers (DUs) represent one major burden for patients with systemic sclerosis (SSc). The objectives of our study were to evaluate blood flow in SSc-DUs with laser speckle contrast analysis (LASCA) and to correlate the skin perfusion to clinical and laboratory data.

Methods: Forty DUs in 31 consecutive patients with SSc according to 2013 ACR/EULAR criteria (20 with limited cutaneous disease, 3 males) were prospectively examined with LASCA. Clinical and laboratory data were collected at the same time. DUs were classified according to clinical features and presence of infection.

Results: At LASCA analysis, patients with diffuse SSc had lower mean values of blood flow compared with those with limited disease at the finger affected by DUs (88.80 vs 44.40, p = 0.036) and at the periulcer area (p = 0.041). The presence of infection was associated to a higher flow at the finger with DU (103.02 vs 58.05 p = 0.04), at the level of ulcer (217.63 vs 67.15, p < 0.001), and at the periulcer area (p = 0.001). The ratio between the blood flow at the ulcer area and the finger base (UA/FB) showed a bimodal trend in patients with infected DUs and in those without infections. Infection was positive correlated to the time of healing (HT) (r = 0.648, p = 0.023), while in DUs without infection a negative correlation to HT (r = - 0.46, p = 0.015) was identified.

Conclusions: This study demonstrates for the first time that the UA/FB ratio may predict the healing time of DUs in SSc patients and may be crucial for the prognostic stratification of patients. Infection remains one of the main predictors of DU healing.Key Points• The prognostic value of laser speckle contrast analysis (LASCA) in patients with digital ulcers (DUs) in systemic sclerosis remains to be clarified.• LASCA may be able to predict the haling time of the digital ulcers.• The presence of infection of the wound bed may greatly influence the LASCA parameters and the healing time of the digital ulcer.
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http://dx.doi.org/10.1007/s10067-019-04662-7DOI Listing
January 2020

Glucocorticoid withdrawal in systemic lupus erythematosus: are remission and low disease activity reliable starting points for stopping treatment? A real-life experience.

RMD Open 2019 11;5(2):e000916. Epub 2019 Jun 11.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objectives: To evaluate the proportion of patients who have successfully withdrawn glucocorticoids (GCs) in a longitudinal cohort of patients with systemic lupus erythematosus (SLE) over a period of 6 years; to evaluate patient characteristics during GC withdrawal in relation to existing definitions of remission and Lupus Low Disease Activity State (LLDAS); and to evaluate the occurrence of flares after GC withdrawal.

Methods: Patients who attempted GC withdrawal were identified for the cohort, and the following information was assessed during withdrawal attempts: date of last disease flare, disease activity and damage and ongoing treatment. Information regarding the occurrence of disease flares after GC withdrawal was also recorded for patients who successfully stopped treatment.Definitions of remission were applied to GC withdrawal in line with European consensus criteria (Definitions of remission in SLE [DORIS]) and LLDAS in line with the Asian Pacific Lupus Consortium definition.

Results: 148 patients were involved in the study; GC withdrawal was attempted in 91 patients (61.5%) with 77 patients (84.6%) successfully stopping GCs. At the beginning of the GC reduction, the majority of patients were in complete or clinical remission (48.9% and 39.6%, respectively). Disease activity was significantly lower in patients who successfully stopped GCs, and the proportion of patients in complete remission was higher (54.2%) with respect to patients who failed in their attempt. Among patients who stopped GCs, 18 flares were recorded after a median of 1 year. The time period since the last flare was shorter in patients who experienced flares with respect to patients who did not flare (mean 0.93 years vs 6.0, p<0.001).

Conclusions: GC withdrawal is an achievable goal in SLE and may be attempted after a long-term remission or LLDAS to protect the patient from disease flares.
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http://dx.doi.org/10.1136/rmdopen-2019-000916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579574PMC
April 2020

Long-Term Retention Rate of Anakinra in Adult Onset Still's Disease and Predictive Factors for Treatment Response.

Front Pharmacol 2019 2;10:296. Epub 2019 Apr 2.

Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy.

Anakinra (ANA) is an effective treatment choice in patients with adult onset Still's disease (AOSD). Variables affecting treatment survival include loss of efficacy or adverse events, but also the decision to discontinue treatment after long-term clinical remission. Aims of this study were: (i) to assess the drug retention rate (DRR) of ANA during a long-term follow-up looking for any difference related to the line of biologic treatment, the concomitant use of conventional disease modifying anti-rheumatic drugs (cDMARDs) and the different type of AOSD (systemic versus chronic articular); (ii) to identify predictive factors of lack of efficacy, loss of efficacy, and ANA withdrawal owing to long-term remission. AOSD patients classified according with Yamaguchi criteria and treated with ANA were retrospectively enrolled in 18 Italian tertiary Centers. Demographic, laboratory, clinical and therapeutic data related to the start of ANA (), the 3-month assessment and the last follow-up visit while on ANA treatment were retrospectively collected and statistically analyzed. One hundred and forty-one AOSD patients (48 males, 93 females) treated with ANA for a mean period of 35.96 ± 36.05 months were enrolled. The overall DRR of ANA was 44.6 and 30.5% at the 60- and 120-month assessments, respectively, with no significant differences between: (i) biologic naïve patients and those previously treated with other biologics (log-rank = 0.97); (ii) monotherapy and concomitant use of cDMARDs (log-rank = 0.45); (iii) systemic and chronic articular types of AOSD (log-rank = 0.67). No variables collected at could predict primary inefficacy, while the number of swollen joints at baseline was significantly associated with secondary inefficacy ( = 0.01, OR = 1.194, C.I. 1.043-1.367). The typical AOSD skin rash was negatively related with ANA withdrawal owing to long-term remission ( = 0.03, OR = 0.224, C.I. 0.058-0.863). Long-term DRR of ANA has been found excellent and is not affected by different lines of biologic treatment, concomitant use of cDMARDs, or type of AOSD. The risk of losing ANA efficacy increases along with the number of swollen joints at the start of therapy, while the typical skin rash is a negative predictor of ANA withdrawal related to sustained remission.
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http://dx.doi.org/10.3389/fphar.2019.00296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454864PMC
April 2019

Tacrolimus in non-Asian patients with SLE: a real-life experience from three European centres.

Lupus Sci Med 2018 2;5(1):e000274. Epub 2018 Nov 2.

Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa, Italy.

Objectives: To analyse the real-life practice on the use of Tacrolimus (TAC) in patients with systemic lupus erythematosus (SLE) from three European SLE referral centres.

Methods: Adult patients with SLE regularly followed at three European referral centres were included. Demographics, cumulative organ involvement, treatment history, Systemic Lupus Disease Activity Index (SLEDAI), laboratory features and physician's judgement were collected at baseline and at 3-6-12 months after starting TAC.

Results: 29 patients were included (89% female, mean age 38±9 years). Ethnicity was predominantly Caucasian (82%), Black African (11%), Hispanic (3.5%) and Caribbean (3.5%). The main indications for TAC prescription were renal involvement (82.7%), arthritis (10.3%), cutaneous manifestations (6.8%), haematological manifestations (6.8%), serositis (3.4%). At 3 months, there was a clinical improvement in 21 patients (72.4%) and 9 of these experienced a complete resolution of symptoms (31%). This corresponds to: (1) a significant decrease in the mean SLEDAI; (2) a significant decrease in the mean 24  hours proteinuria; a significant increase in C3 and stable creatinine values. At 6 months (n=25), the physician declared an improvement in 19 patients (76%) and a complete resolution of symptoms in 9 (36%). The same trend was observed at 12 months of follow-up. TAC was discontinued in nine pts (31%); reasons for discontinuation were inefficacy (13.8%), drug intolerance (10%) and disease remission (6.9%).

Conclusions: Despite the limitation due to the small number of patients and the uncontrolled nature of the study, these data show that TAC can be considered a valid therapeutic option in patients with SLE, especially for renal involvement.
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http://dx.doi.org/10.1136/lupus-2018-000274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257376PMC
November 2018

Imaging of joints in systemic lupus erythematosus.

Clin Exp Rheumatol 2018 Sep-Oct;36 Suppl 114(5):68-73. Epub 2018 Oct 1.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Musculoskeletal symptoms are among the most common manifestations in patients with systemic lupus erythematosus (SLE), being reported in up to 95% of patients; joint and tendon involvement can range from arthralgia to severe deforming arthropathy; while myositis a rare manifestation, comorbid fibromyalgia is reported in up to 40% of SLE patients. All these manifestations have a significant impact on the patients' quality of life, possibly leading to disability and functional impairment in daily living activities. In recent years, thanks to the availability of new imaging techniques for the assessment of tendon and joint pathologies, the approach to the definition and characterisation of these manifestations in SLE is constantly evolving. In this review we will therefore illustrate the state of the art of imaging techniques in the assessment of joint involvement in SLE, focusing on ultrasounds (US) and magnetic resonance (MRI), discussing their advantages, drawbacks and possible future developments. The main findings that emerge from the recent literature is that imaging studies may allow a more accurate definition of disease subtypes revealing an unexpected higher prevalence of joint and tendon involvement with respect to what known by clinical evaluation and standard radiography. Indeed, US and MRI also made possible the identification of joints and tendons pathologies in patients with no or very mild clinical symptoms. On the other hand, the interpretation of some findings remains uncertain, as well as the validity and feasibility of this analysis in clinical practice. Thus, further studies should clarify the clinical meaning of subclinical abnormalities detected in US and MRI scans and their impact on the long-term outcomes.
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January 2019

Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study.

Clin Rheumatol 2018 Aug 17;37(8):2233-2240. Epub 2018 May 17.

Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Udine, Italy.

A few studies have reported the safety profile of interleukin (IL)-1 blockers from real life. The aim of this study is to describe anakinra (ANA) and canakinumab (CAN) safety profile in children and adults, based on data from a real-life setting. Demographic, clinical, and therapeutic data from patients treated with ANA and CAN were retrospectively collected and analyzed. Four hundred and seventy five patients were enrolled; ANA and CAN were prescribed in 421 and 105 treatment courses, respectively. During a mean follow-up of 24.39 ± 27.04 months, 89 adverse events (AE) were recorded; 13 (14.61%) were classified as serious AE (sAE). The overall estimated rate of AE and sAE was 8.4 per 100 patients/year. Safety concerns were more frequent among patients aged ≥ 65 years compared with patients < 16 years (p = 0.002). No differences were detected in the frequency of safety concerns between monotherapy and combination therapy with immunosuppressants (p = 0.055), but a significant difference was observed when injection site reactions were excluded from AE (p = 0.01). No differences were identified in relation to gender (p = 0.462), different lines of biologic therapy (p = 0.775), and different dosages (p = 0.70 ANA; p = 0.39 CAN). The overall drug retention rate was significantly different according to the occurrence of safety concerns (p value < 0.0001); distinguishing between ANA and CAN, significance was maintained only for ANA (p < 0.0001 ANA; p > 0.05 CAN). Treatment duration was the only variable associated with onset of AE (OR = 0.399 [C.I. 0.250-0.638], p = 0.0001). ANA and CAN have shown an excellent safety profile; the risk for AE and sAE tends to decrease over time from the start of IL-1 inhibition.
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http://dx.doi.org/10.1007/s10067-018-4119-xDOI Listing
August 2018

Remission and low disease activity in systemic lupus erythematosus: an achievable goal even with fewer steroids? Real-life data from a monocentric cohort.

Lupus Sci Med 2018 27;5(1):e000234. Epub 2018 Feb 27.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objectives: To evaluate what proportion of patients fulfil the DORIS definition of remission, the definition of lupus low disease activity state (LLDAS) and LLDAS with a glucocorticoid (GC) dosage ≤5 (LLDAS5) in a longitudinal monocentric cohort of patients with SLE; to identify predictors of sustained remission and LLDAS attainment; to evaluate the effect of sustained remission and LLDAS on damage accrual over a period of 5 years and compare the two conditions in terms of clinical outcomes.

Methods: Retrospective analysis of data prospectively collected from patients with SLE followed from 2012 to 2016.

Results: 115 patients were included in this analysis. At baseline, 72% of patients were on LLDAS and almost all patients also fulfilled the LLDAS5 definition; 45% of patients were in remission on treatment, 12% were in remission off treatment, 26% were in complete remission on treatment, 2% were in complete remission off treatment. Disease activity at baseline was the strongest predictor of subsequent LLDAS and remission; the presence of joint and cutaneous manifestations was associated with a minor likelihood to achieve LLDAS or remission during follow-up.Patients in remission and LLDAS for the whole follow-up period accrued significantly less organ damage; on the contrary, patients who maintained all kinds of remissions or LLDAS for less than 50% of the time did not show any differences in damage accrual with respect to the rest of the cohort.

Conclusion: Remission and LLDAS, even with reduced GC use, are an achievable goal in clinical practice; sustained LLDAS and remission are both associated with reduced damage accrual.
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http://dx.doi.org/10.1136/lupus-2017-000234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844382PMC
February 2018

Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study.

Front Pharmacol 2017 13;8:369. Epub 2017 Jun 13.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of PisaPisa, Italy.

Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD). To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity. One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations ( < 0.0001), and Pouchot's score was found to be significantly reduced at all time points ( < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points ( < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.
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http://dx.doi.org/10.3389/fphar.2017.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469286PMC
June 2017

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study.

Front Pharmacol 2016 24;7:380. Epub 2016 Oct 24.

Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, Seconda Università degli Studi of Naples Naples, Italy.

Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0-2.0 mg/kg/day) among adults and 2-4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.
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http://dx.doi.org/10.3389/fphar.2016.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076463PMC
October 2016

One year in review 2016: systemic sclerosis.

Clin Exp Rheumatol 2016 Sep-Oct;34 Suppl 100(5):3-13. Epub 2016 Jul 18.

Rheumatology Unit, University of Pisa, Italy.

Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year, novel insights into the pathogenesis, diagnosis and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published over the last year.
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January 2017

Systemic sclerosis: a critical digest of the recent literature.

Clin Exp Rheumatol 2015 Jul-Aug;33(4 Suppl 91):S3-14. Epub 2015 Aug 5.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Systemic sclerosis is a complex chronic disease characterised by chronic multisystem involvement of skin and internal organs. We reviewed all the articles published during the last 12 months on systemic sclerosis and in this article we provide a critical analysis of the most relevant studies regarding the pathogenesis, classification and management of the disease.
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October 2015

Epidemiology and management of neuropsychiatric disorders in Behçet's syndrome.

CNS Drugs 2015 Mar;29(3):189-96

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy,

Behçet's syndrome (BS) is a systemic, chronic, relapsing vasculitis, typically characterized by recurrent orogenital ulcers, ocular inflammation and skin manifestations; articular, vascular, gastroenteric and neurological involvement may also occur. Besides the other clinical features of BS, it seems relatively frequent that patients with BS develop a neurobehavioural syndrome, characterized by euphoria, bipolar disorders and paranoid attitudes, loss of insight/disinhibition, and indifference to their disease, defined as 'neuro-psycho-BS'. To date, the pathogenetic mechanism underlying neuro-psycho-BS has not been determined. It may be secondary to organic neurological involvement, or it may be related to poor quality of life and the relapsing course of the disease. Another engaging theory suggests that it could be related to the frequent observation of psychiatric symptoms during relapses or, in some cases, in the phases preceding reactivation of the disease; these elements suggest that psychiatric disorders in BS could represent a crucial element, whether a psychiatric subset or a distinct clinical feature of the disease. Moreover, it has been reported that cognitive impairment in BS can be seen with or without central nervous system involvement. Globally, psychiatric symptoms have been described as being multifaceted, ranging from anxiety disorders to depressive-bipolar disorders or to psychotic ones. In addition, some psychological characteristics of BS patients seem to predispose them to maladaptive stress management, which may lead to stress-related disorders, including anxiety and depression. Therefore, the aims of this review are to explore the epidemiology of neuro-psycho-BS by evaluating the relationship between the stress system and the multifaceted psychiatric manifestations in BS, and to summarize the therapeutic strategy used.
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http://dx.doi.org/10.1007/s40263-015-0228-0DOI Listing
March 2015

Isolated aortitis versus giant cell arteritis: are they really two sides of the same coin?

Clin Exp Rheumatol 2014 May-Jun;32(3 Suppl 82):S55-8. Epub 2014 May 15.

Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Objectives: The aim of the study was to compare epidemiological data, clinical findings and results of investigations in patients with isolated aortitis and those with giant cell arteritis (GCA) to establish whether patients with isolated aortitis differ from those with GCA.

Methods: We reviewed the medical notes of all patients consecutively seen in two Rheumatology centres in the last two decades with a suspicion of GCA, searching for cases characterised by abnormal [18F] fluorodeoxyglucose (FDG) PET uptake of the aorta. 'Isolated aortitis' was defined as increased FDG uptake in the aorta not explained by atherosclerosis in the absence of FDG uptake in other large vessels.

Results: Comparing the epidemiological and clinical data of patients with isolated arteritis with those with GCA, we observed many statistical significant differences. First of all, the male/female ratio was reversed, with a predominant male involvement in isolated arteritis. Moreover, the mean age of patients with isolated arteritis was significantly lower than that of GCA patients (62 vs. 78.4 yrs; p<0.0001). None of the patients with isolated aortitis presented at any time of the disease course the typical symptoms of GCA, while in a low percentage of cases constitutional symptoms represented the only clinical features. Beside the aortic arch, the sites more frequent involved were the thoracic and abdominal tracts, in all cases without an uptake of the aortic branches.

Conclusions: It is not known whether our patients with isolated aortitis represent variants of GCA or TA, nor is it known how they will evolve, but we can certainly conclude that these patients have a different epidemiologic and clinical profile, and do not necessarily represent two sides of the same coin.
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July 2014

Large- and small-vessel vasculitis: a critical digest of the 2010-2011 literature.

Clin Exp Rheumatol 2012 Jan-Feb;30(1 Suppl 70):S130-8. Epub 2012 May 11.

Rheumatology Unit, Department of Internal Medicine, University of Pisa, Italy.

The last two years have been marked by significant achievement in the identification of the basic mechanisms of systemic vasculitis and in the translation of these mechanisms into targeted therapies. More specifically, new insights into the environmental, cellular, and genetic factors involved in the pathogenesis of systemic vasculitis have been provided. Consequently, several studies focused on the development of novel strategies to achieve and maintain clinical remission in small- and large-vessel vascultis, including relevant large multicentre trials, have been promoted. The highlights of these studies, their potential clinical implications and the unmet needs, which are still to be addressed, are summarised in this review.
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August 2012
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