Papers by Alessandra Bortoluzzi
Frontiers in Medicine
Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) is one of the most severe... more Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) is one of the most severe manifestations of the disease that has a heavy impact on patient's functioning, quality of life, and disease outcome. The prevalence is highly variable and the clinical phenotypes vary from common syndromes to rare NP entities. Its occurrence may be the result of a primary manifestation of SLE, secondary to other conditions (such as infections or metabolic disturbances) or the effect of concomitant comorbidities that often complicate the disease course. Correct attribution of NP events may pose diagnostic challenges and it is a critical factor in selecting the correct management. Although there is still no diagnostic gold standard to rightly diagnose NPSLE syndromes, great advances have been made in improving the clinician judgment in the evaluation process. In this narrative review, we present and discuss available evidence concerning NPSLE with a special focus on the attribution models developed using composite decision rules to ascribe NP events to SLE.
Arthritis Research & Therapy, 2016
Adenosine is a purine nucleoside implicated in the regulation of the innate and adaptive immune s... more Adenosine is a purine nucleoside implicated in the regulation of the innate and adaptive immune systems, acting through its interaction with four cell surface receptors: A1, A2A, A2B, and A3. There is intense interest in understanding how adenosine functions in health and during disease, but surprisingly little is known about the actual role of adenosine-mediated mechanisms in systemic lupus erythematosus (SLE). With this background, the aim of the present study was to test the hypothesis that dysregulation of A1, A2A, A2B, and A3 adenosine receptors (ARs) in lymphocytes of patients with SLE may be involved in the pathogenesis of the disease and to examine the correlations between the status of the ARs and the clinical parameters of SLE. ARs were analyzed by performing saturation-binding assays, as well as messenger RNA and Western blot analysis, with lymphocytes of patients with SLE in comparison with healthy subjects. We tested the effect of A2AAR agonists in the nuclear factor kB (NF-kB) pathway and on the release of interferon (IFN)-α; tumor necrosis factor (TNF)-α; and interleukin (IL)-2, IL-6, IL-1β, and IL-10. In lymphocytes obtained from 80 patients with SLE, A2AARs were upregulated compared with those of 80 age-matched healthy control subjects, while A1, A2B, and A3 ARs were unchanged. A2AAR density was inversely correlated with Systemic Lupus Erythematosus Disease Activity Index 2000 score disease activity through time evaluated according to disease course patterns, serositis, hypocomplementemia, and anti-double-stranded DNA positivity. A2AAR activation inhibited the NF-kB activation pathway and diminished inflammatory cytokines (IFN-α, TNF-α, IL-2, IL-6, IL-1β), but it potentiated the release of anti-inflammatory IL-10. These data suggest the involvement of A2AARs in the complex pathogenetic network of SLE, acting as a modulator of the inflammatory process. It could represent a compensatory pathway to better counteract disease activity. A2AAR activation significantly reduced the release of proinflammatory cytokines while enhancing those with anti-inflammatory activity, suggesting a potential translational use of A2AAR agonists in SLE pharmacological treatment.
Expert Opinion on Orphan Drugs, 2016
Rheumatology, 2016
This study aimed to estimate the prevalence of US-detected tenosynovitis in RA patients in clinic... more This study aimed to estimate the prevalence of US-detected tenosynovitis in RA patients in clinical remission and to explore its clinical correlates. A total of 427 RA patients in clinical remission were consecutively enrolled from 25 Italian rheumatology centres. Tenosynovitis and synovitis were scored by US grey scale (GS) and power Doppler (PD) semi-quantitative scoring systems at wrist and hand joints. Complete clinical assessment was performed by rheumatologists blinded to the US results. A flare questionnaire was used to assess unstable remission (primary outcome), HAQ for functional disability and radiographic erosions for damage (secondary outcomes). Cross-sectional relationships between the presence of each US finding and outcome variables are presented as odds ratios (ORs) and 95% CIs, both crude and adjusted for pre-specified confounders. The prevalence of tenosynovitis in clinical remission was 52.5% (95% CI 0.48, 0.57) for GS and 22.7% (95% CI 0.19, 0.27) for PD, while the prevalence of synovitis was 71.6% (95% CI 0.67, 0.76) for GS and 42% (95% CI 0.37, 0.47) for PD. Among clinical correlates, PD tenosynovitis associated with lower remission duration and morning stiffness while PD synovitis did not. Only PD tenosynovitis showed a significant association with the flare questionnaire [OR 1.95 (95% CI 1.17, 3.26)]. No cross-sectional associations were found with the HAQ. The presence of radiographic erosions associated with GS and PD synovitis but not with tenosynovitis. US-detected tenosynovitis is a frequent finding in RA patients in clinical remission and associates with unstable remission.
Rheumatology (Oxford, England)
To analyse risk factors and comorbidities potentially associated with CNS involvement in a large ... more To analyse risk factors and comorbidities potentially associated with CNS involvement in a large cohort of Italian patients affected by SLE. A number of generic (not strictly SLE related) and specific (disease related) risk factors to which all patients have been exposed in the span of 5 years before the first neuropsychiatric (NP) event or before the last available observation were checked for and their distribution was analysed in 959 SLE patients with and without NP involvement; all the first NP events that occurred in a time frame of 10 years were recorded and categorized as SLE related or SLE unrelated. Three hundred and twenty-six SLE patients with and 633 SLE patients without NP manifestations were included in the study. A total of 469 NP events were recorded. Headache (26.1%), cerebrovascular events (22.7%), mood disorders (8.9%), seizures (14.4%) and cognitive dysfunctions (9.5%) were the most frequent SLE-related NP events. More risk factors [mean 4.52 (2.44) vs 3.73 (2.01...
Annals of the Rheumatic Diseases, 2012
Objective. To assess the relationship between clinical picture and neuroimaging in patients affec... more Objective. To assess the relationship between clinical picture and neuroimaging in patients affected by SLE with and without neuropsychiatric (NP) involvement. Methods. One hundred and seven SLE patients including 66 with NP involvement (NPSLE) with focal or diffuse presentation and 41 without underwent single photon emission computed tomography (SPECT) and MRI. Results. After stratification for diffuse or focal NP involvement, in the 52 patients with diffuse presentation, abnormalities detected with MRI or SPECT did not differ from patients without NP; however, after combining the two techniques, a normal result was more frequently observed in patients without NP involvement (P ¼ 0.010). In the 14 patients with focal presentation, MRI alone and concordant abnormal MRI plus SPECT were more frequently detected in the NPSLE group; again normal findings by both techniques simultaneously applied were more frequently found in SLE patients without NP involvement. White matter hyperintense T2-weighted lesions were the most frequent MRI abnormal findings in both groups, but the presence of multiple lesions (>5) involving both the hemispheres at subtentorial level was limited to NPSLE patients. Multifocal hypoperfused SPECT areas were more frequently observed in frontal and parietal lobes of NPSLE. Conclusions. Combining SPECT and MRI appears more useful than the two techniques alone and may help the clinician in the assessment of patients with NP involvement since normal findings contemporarily detected by these two techniques have been rarely observed in patients with NP involvement especially in those with focal manifestations where MRI and SPECT were never simultaneously normal.
Rheumatology, 2012
To analyse risk factors and comorbidities potentially associated with CNS involvement in a large ... more To analyse risk factors and comorbidities potentially associated with CNS involvement in a large cohort of Italian patients affected by SLE. A number of generic (not strictly SLE related) and specific (disease related) risk factors to which all patients have been exposed in the span of 5 years before the first neuropsychiatric (NP) event or before the last available observation were checked for and their distribution was analysed in 959 SLE patients with and without NP involvement; all the first NP events that occurred in a time frame of 10 years were recorded and categorized as SLE related or SLE unrelated. Three hundred and twenty-six SLE patients with and 633 SLE patients without NP manifestations were included in the study. A total of 469 NP events were recorded. Headache (26.1%), cerebrovascular events (22.7%), mood disorders (8.9%), seizures (14.4%) and cognitive dysfunctions (9.5%) were the most frequent SLE-related NP events. More risk factors [mean 4.52 (2.44) vs 3.73 (2.01); P < 0.0001] were observed in patients with than without NP involvement. Overall, aPLs, LA and APS were factors more strongly associated with NP involvement. In SLE, NP involvement and aPLs were confirmed as closely related. Furthermore, other modifiable generic risk factors, such as hypertension, carotid vasculopathy and dyslipidaemia, appeared to be related to the occurrence of cerebral vascular accident (CVA) and cognitive dysfunctions, suggesting the need for a more intensive preventive strategy to optimize the management of NP lupus.
Rheumatology, 2010
To investigate the role of the TNF-related apoptosis-inducing ligand-osteoprotegerin (TRAIL-OPG) ... more To investigate the role of the TNF-related apoptosis-inducing ligand-osteoprotegerin (TRAIL-OPG) system in the pathogenesis of limited SSc (lSSc). Circulating levels of TRAIL and of its soluble receptor OPG were measured by ELISA in serum samples obtained from 50 lSSc patients and 50 healthy controls. TRAIL serum levels in lSSc patients were similar to those of healthy controls, whereas the OPG serum levels were significantly increased (P < 0.0001). According to different subgroups of lSSc patients, TRAIL was not statistically different between each group and healthy controls; concerning OPG, the statistically different value was also maintained when comparing each single lSSc group with the whole control population. OPG serum levels, but not TRAIL, are elevated in lSSc patients. Since OPG binding to TRAIL inhibits TRAIL-TRAIL receptor interaction, the relative concentrations of these two molecules in the local micro-environment has to be considered. In this setting, OPG increase in lSSc patients may produce a detrimental effect by counteracting the vasoprotective activity of TRAIL. The TRAIL : OPG ratio and their relative levels of expression in lSSc patients should be taken into consideration as a possible novel marker of vascular damage.
Lupus, 2011
To assess the utility of a combined neuroimaging approach in the follow up of patients affected b... more To assess the utility of a combined neuroimaging approach in the follow up of patients affected by systemic lupus erythematosus (SLE) with and without neuropsychiatric (NP) involvement. Patients who underwent a first combined brain conventional magnetic resonance imaging (cMRI) and single photon emission computed tomography (SPECT) and later repeated the same examinations between 2001 and 2008 were retrieved from a large database. Clinical and neuroimaging data were analysed and their relationships evaluated at baseline and at follow up. Fifty SLE patients (38 with and 12 without NP involvement, mean age 36.8 yrs and mean disease duration at first instrumental evaluation 5.5 yrs) were enrolled. At baseline, the majority of them had a diffuse pattern of NP involvement. After a mean follow up period of 4 years all patients repeated neuroimaging and clinical evaluation. In 23 patients (22 with and 1 without NP manifestations at baseline) a new NP event occurred. Overall, neuroimaging remained unchanged or improved, but in some cases it worsened. No correlations were found between instrumental findings and clinical picture. In this study, the clinical features at baseline appeared to be a better predictor of future NP events than morphological and functional neuroimaging. Therefore the utility of repeating a combined instrumental evaluation (cMRI and SPECT) may be debatable especially for patients with diffuse NP involvement where the decision to perform serial combined neuroimaging examinations should be carefully assessed and based mainly on clinical judgement.
The Journal of Rheumatology, 2010
To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related ap... more To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) and the therapeutic response to disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA). Circulating levels of TRAIL and its soluble receptor OPG were measured by ELISA in paired serum samples obtained from 66 patients with early RA at their first visit (baseline) and after 1 year of therapy. Levels of TRAIL and OPG were analyzed in relation to the clinical response, defined by the 28-joint count Disease Activity Score (DAS28). Both serum TRAIL and OPG increased after DMARD therapy. Baseline levels of TRAIL, but not OPG, were significantly higher (p < 0.05) in the patients that achieved a clinical response by DAS28 after 1 year of therapy, versus patients without clinical response to DMARD. Baseline serum levels of TRAIL were higher (p < 0.01) in rheumatoid factor-negative patients. Our data suggest that the basal level of circulating TRAIL is an important determinant in the therapeutic response to DMARD in patients with early RA.
Rheumatology (Oxford, England), Jan 21, 2014
The aim of this study was to develop and validate an algorithm to assist the attribution of neuro... more The aim of this study was to develop and validate an algorithm to assist the attribution of neuropsychiatric (NP) events to underlying disease in SLE patients. Phase 1 identified and categorized candidate items to be included in the algorithm for the attribution of an NP event to SLE and their relative weights through a literature-informed consensus-driven process. Using a retrospective training cohort of SLE, phase 2 validated items selected in phase 1 and refined weights through a data-driven process, fitting items as independent variables and expert evaluation (clinical judgement) as reference standard in logistic models. Phase 3 consisted of a validation process using an external multicentre retrospective SLE cohort. Phase 1 identified four different items: timing of the NP event, type of event, confounding factors and favouring factors. The training and validating cohorts included 228 and 221 patients, respectively. Each patient experienced at least one NP event characterized u...
Clinical and experimental rheumatology
Digital ulcers (DU) occur in about 50% of systemic sclerosis (SSc) patients. Scleroderma DU are r... more Digital ulcers (DU) occur in about 50% of systemic sclerosis (SSc) patients. Scleroderma DU are responsible for chronic pain and disability with the need of systemic and local treatments. Recently, capillaroscopic skin ulcer risk index (CSURI) has been validated as useful tool in predicting the appearance of new scleroderma ulcers and/or persistence of non-healing lesions, within 3 months from capillaroscopy evaluation. Since the image length of 1.57 mm might represent a critical factor for CSURI calculation, the present study aimed to evaluate the reliability of CSURI using three different videocapillaroscopy devices with distinct image widths. One hundred and seventy-six unselected SSc patients were consecutively enrolled for the study during a six-month period, using three different capillaroscopy devices (image widths of 1.33, 1.57, and 1.70 mm). After a three month-follow-up new DU or persisting non-healing ulcers were observed in 46/176 patients (26.1%). The receiver operating...
BioMed Research International, 2014
Objective. To evaluate the involvement of the bursa located next to the head of the 5th metatarsa... more Objective. To evaluate the involvement of the bursa located next to the head of the 5th metatarsal bone in patients with psoriatic arthritis (PsA) in comparison with the other seronegative spondyloarthritis (SpA). Methods. All patients with PsA seen during a period of 24 months were enrolled. The control group included healthy subjects and patients with the other SpA. All subjects underwent clinical and ultrasound (US) examination of the lateral surface of the 5th metatarsal. Results. 150 PsA patients (88 M; 62 F), 172 SpA (107 M; 65 F), and 95 healthy controls (58 M; 37 F) were evaluated. Based on clinical and US evaluation, bursitis was diagnosed in 17/150 (11.3%) PsA patients but in none of the SpA ( < 0.0001) and healthy ( = 0.0002) controls. In detecting bursitis, US was more sensitive than clinical examination, although the difference did not reach statistical significance ( = 0.09). Conclusion. The bursa of the 5th metatarsophalangeal joint appears to be involved in PsA more frequently than by chance. If confirmed by other studies, this finding could be considered as a distinctive clinical sign of PsA, useful for differential diagnosis with the other SpA. In asymptomatic patients, US proved to be more sensitive in the detection of bursitis.
Rheumatology International, 2012
To evaluate, by a retrospective cross-sectional case-control study from a single center, the dist... more To evaluate, by a retrospective cross-sectional case-control study from a single center, the distribution of a number of factors and comorbidities potentially related to central nervous system involvement in SLE Italian patients, a number of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;generic&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; (i.e. not strictly SLE related) and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;specific&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; (i.e. SLE related) risk factors were checked and their distribution analyzed in SLE patients with (NPSLE) and without (SLE) neuropsychiatric (NP) involvement. One hundred and fifty-three SLE patients with NP involvement observed from 1999 to 2008 and 247 SLE patients without NP manifestations, matched for sex, age and disease duration were included in the study. A neuropsychiatric (NP) event represented the heralding symptom of the disease in 40.5% of NPSLE. Headache, cerebrovascular events, mood disorders and seizures were the most frequent NP manifestations. NPSLE patients had a major cumulative number of the investigated factors than controls without NP involvement. Antiphospholipid antibodies (aPL), lupus anticoagulant (LA), Antiphospholipid antibodies syndrome (APS), Raynaud&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s phenomenon, smoke, assumption of contraceptives and higher cumulative dose of glucocorticosteroids (GC) were significantly more commonly observed among NPSLE. APS and systemic arterial hypertension were more frequently detected among patients with focal NP manifestations, especially cerebrovascular events. aPL, LA, APS, Raynaud&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s phenomenon, smoke, contraceptives intake and higher cumulative dose of GC did prove more frequently detected in NPSLE patients than in controls. In particular, overall, arterial hypertension should be regarded as a potential independent &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;risk factor&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; for focal involvement, especially for cerebrovascular events.
Advances in Therapy, 2014
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Papers by Alessandra Bortoluzzi