Publications by authors named "Bruno Frediani"

193 Publications

Giant cell arteritis presenting as a stroke in the internal carotid artery territory: a case-based review.

Reumatologia 2021 27;59(2):121-125. Epub 2021 Apr 27.

Department of Medicine, Surgery and Neurosciences, Rheumatology Unit, University of Siena, Italy.

Giant cell arteritis (GCA) is a large-vessel vasculitis, typically affecting the aorta and its branches. The involvement of vertebral and internal carotid arteries occurs in a limited number of cases, and stroke as a presenting symptom of GCA is extremely unusual: this subset of the disease has a poor prognosis and rarely responds to immunosuppression. We report the case of a 70-year-old woman, who presented to the Emergency Department for ischemic stroke, which appeared to be the first and only symptom of GCA. The prompt administration of steroids and tocilizumab (TCZ) led to clinical and radiological resolution, with no residual disability at 6-month follow-up. Our case-based review, highlighting the rarity of a large vessel vasculitis presenting only with a cerebrovascular accident, provides new evidence for the efficacy of TCZ even in more unusual varieties of GCA: in these cases, TCZ should be immediately prescribed, in order to prevent mortality and severe long-term morbidity.
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http://dx.doi.org/10.5114/reum.2021.105414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103407PMC
April 2021

Drug survival of anakinra and canakinumab in monogenic autoinflammatory diseases: observational study from the International AIDA Registry.

Rheumatology (Oxford) 2021 May 7. Epub 2021 May 7.

Research Center of Systemic Auto inflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Objectives: To investigate survival of interleukin (IL)-1 inhibitors in monogenic autoinflammatory disorders (mAID) through drug retention rate (DRR) and identify potential predictive factors of drug survival from a real-life perspective.

Patients And Methods: Multicentre retrospective study analyzing patients affected by the most common mAID treated with anakinra or canakinumab. Survival curves were analyzed with the Kaplan-Meier method. Statistical analysis included a Cox-proportional hazard model to detect factors responsible for drug discontinuation.

Results: Seventy-eight patients for a total of 102 treatment regimens were enrolled. The mean treatment duration was 29.59 months. The estimated DRR of IL-1 inhibitors at 12, 24, and 48 months of follow-up was 75.8%, 69.7% and 51.1%, respectively. Patients experiencing an adverse event had a significantly lower DRR (p = 0.019). In contrast, no significant differences were observed between biologic-naïve patients and those previously treated with biologic drugs (p = 0.985) Patients carrying high-penetrance mutations exhibited a significantly higher DRR compared with those with low-penetrance variants (p = 0.015). Adverse events were the only variable associated with a higher hazard of treatment withdrawal (HR 2.573 [CI: 1.223-5.411], p = 0.013) on regression analysis. A significant glucorticoid-sparing effect was observed (p < 0.0001).

Conclusions: IL-1 inhibitors display an excellent long-term effectiveness in terms of DRR, and their survival is not influenced by the biologic line of treatment. They display a favorable safety profile, that deserves however a close monitoring given its impact on treatment continuation. Special attention should be paid to molecular diagnosis and mutation penetrance, as patients carrying low-penetrance variants are more likely to interrupt treatment.
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http://dx.doi.org/10.1093/rheumatology/keab419DOI Listing
May 2021

Efficacy of belimumab monotherapy in high infectious risk patient affected by lupus nephritis.

Rheumatol Adv Pract 2021 17;5(1):rkab023. Epub 2021 Apr 17.

Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

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http://dx.doi.org/10.1093/rap/rkab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053684PMC
April 2021

Retention rate of a second line with a biologic DMARD after failure of a first-line therapy with abatacept, tocilizumab, or rituximab: results from the Italian GISEA registry.

Clin Rheumatol 2021 Apr 21. Epub 2021 Apr 21.

Department of Emergency and Organ Transplantation, Rheumatology Unit, University of Bari, Bari, Italy.

Objectives: EULAR recommendations do not suggest which biologic disease-modifying anti-rheumatic drug (bDMARD) should be preferred after failure of a first bDMARD in the treatment of rheumatoid arthritis (RA). In particular, few data are available regarding the effectiveness of a second-line bDMARD after failure of abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX). The aim of this study was to analyze the retention rate of a second line with tumor necrosis factor inhibitors (TNFi) or other mechanisms of action (MoAs), after the failure of either RTX, TCZ, or ABA.

Methods: Two hundred and seventy-eight RA patients from the Italian GISEA registry were included in the study. RTX was the first bDMARD in 18% of patients, ABA in 45.7%, and TCZ in 36.3%, while the second bDMARD was a TNFi (group 1) in 129 patients and an agent with a different MoA (group 2) in 149.

Results: During a median follow-up of 22 months (IQR 68), 129 patients discontinued their treatment; patients of group 1 discontinued the treatment more frequently than patients of group 2 (p<0.001) with retention rates of 33.6±5.7% and 63.6±4.6% after 104 weeks for group 1 and group 2, respectively (p<0.001). At multivariate analysis, the mechanism of action was the only predictor for the maintenance in therapy.

Conclusions: According to our data, ABA, RTX, and TCZ seem to maintain a good retention rate also when used as a second-line therapy, suggesting their use after the failure of a non-TNFi as first-line therapy. However, specifically designed studies are needed to evaluate the more appropriate therapeutic strategies in RA, according to the first-line drug, including new targeted synthetic DMARDs. Key Points • A large proportion of rheumatoid arthritis patients fail the first biologic DMARD. • Few data are available about the efficacy of biologic DMARD after the failure of a non-TNF inhibitor. • Abatacept, rituximab, or tocilizumab seem to maintain a good retention rate after the failure of a first-course therapy with a non-TNF inhibitor.
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http://dx.doi.org/10.1007/s10067-021-05734-3DOI Listing
April 2021

A novel grey Scale and Power Doppler ultrasonographic score for idiopathic inflammatory myopathies: Siena Myositis Ultrasound Grading Scale.

Rheumatology (Oxford) 2021 Apr 11. Epub 2021 Apr 11.

Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.

Objectives: No clear-cut guidelines exist about the use of diagnostic procedures for idiopathic inflammatory myopathies (IIM) and only scanty and conflicting data report the use of ultrasound (US). In this regard, we aimed to assess if grey-scale (GS) and Power Doppler (PD) US, graded with a 0-3-points-scale, may be a reliable tool in a cohort of patients affected by IIM.

Methods: All patients underwent US examination of both thighs in axial and longitudinal scans. Edema and atrophy, both assessed in GS, and PD, were graded with a 0-3-points-scale. Spearman test was used to identify the correlations between US and clinical and serological variables.

Results: A total of 20 patients was included. Six and 2 of them were evaluated twice and 3 times, respectively. Muscle edema was found to be directly correlated with physician global assessment (PhGA), serum myoglobin and PD and negatively with disease duration. PD score was positively correlated to PhGA and negatively to disease duration. Muscle atrophy directly correlated with Myositis Damage Index, disease duration and patients' age. The single-thigh sub-analysis evidenced a direct correlation between PD score and Manual Muscle Test.

Conclusions: In our cohort, we found that edema and PD are strictly related to early, active myositis, suggesting that an inflamed muscle should appear swollen, thickened and with Doppler signal. Conversely, muscle atrophy reflects the age of the patient and the overall severity of the disease. Such findings shed a new, promising, light in the role of US in diagnosis and monitoring of IIMs.
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http://dx.doi.org/10.1093/rheumatology/keab340DOI Listing
April 2021

Clinical profile and evolution of patients with juvenile-onset Behçet's syndrome over a 25-year period: insights from the AIDA network.

Intern Emerg Med 2021 Apr 9. Epub 2021 Apr 9.

Research Center of Systemic Auto Inflammatory Diseases, Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Rheumatology Unit, Policlinico "Le Scotte", Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Viale Bracci 16, 53100, Siena, Italy.

Behçet's syndrome (BS) represents an understudied topic in pediatrics: the main aims of our study were to characterize demographic and clinical features of a cohort of BS patients with juvenile-onset managed in three tertiary referral centers in Italy, evaluate their evolution in the long-term, and detect any potential differences with BS patients having an adult-onset. Medical records of 64 juvenile-onset and 332 adult-onset BS followed-up over a 2-year period were retrospectively analyzed and compared. Mean age ± SD of first symptom-appearance was 10.92 ± 4.34 years with a female-to-male ratio of 1.06:1. Mucocutaneous signs were the most frequent initial manifestations, followed by uveitis. Throughout the disease course, genital aphthae (76.56%) and pseudofolliculitis (40.63%) prevailed among the mucocutaneous signs, while major organ involvement was represented by gastrointestinal and ocular involvement (43.75 and 34.38%, respectively). No significant differences emerged for both mucocutaneous signs and specific major organ involvement between juvenile-onset and adult BS patients. After excluding nonspecific abdominal pain, juvenile-onset BS patients were less frequently characterized by the development of major organ involvement (p = 0.027). Logistic regression detected the juvenile-onset as a variable associated with reduced risk of long-term major organ involvement (OR 0.495 [0.263-0.932], p = 0.029). In our cohort, juvenile-onset BS resembled the clinical spectrum of adult-onset patients. Pediatric patients with a full-blown disease at onset showed a more frequent mucocutaneous involvement. In addition, patients with juvenile-onset seemed to develop less frequently major organ involvement and had an overall less severe disease course.
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http://dx.doi.org/10.1007/s11739-021-02725-9DOI Listing
April 2021

Prognostic role of KL-6 in SSc-ILD patients with pleuroparenchymal fibroelastosis.

Eur J Clin Invest 2021 Mar 23:e13543. Epub 2021 Mar 23.

Respiratory Diseases and Lung Transplantation, Department of Medical and Surgical Sciences & Neurosciences, Siena University Hospital, Siena, Italy.

Background: Krebs von den Lungen-6 (KL-6) is a high-molecular-weight (200kDa) glycoprotein proposed as a diagnostic biomarker for differentiating interstitial lung disease (ILD). Systemic sclerosis (SSc) is a rare immune-mediated disorder, and ILD is the leading cause of morbidity and mortality. Pleuroparenchymal fibroelastosis (PPFE) has been described to have a poor prognosis in SSc-ILD patients. This study undertook to compare serial changes in KL-6 in SSc-ILD patients with and without PPFE, to verify its prognostic value as a disease biomarker.

Materials And Methods: Twenty-five SSc-ILD patients (median IQR, 62 (56-58); 20% males) were retrospectively enrolled. 12 SSc-ILD patients (48%) had also a radiological diagnosis of PPFE. Serum KL-6 concentrations were measured by KL-6 reagent assay (Fujirebio Europe, Ghent, Belgium).

Results: Serum KL-6 measurements were increased in SSc-ILD patients with and without PPFE compared with healthy controls (P < .0001). Comparative analysis of the rate of variation of KL-6 over the 6 years of follow-up was performed by serial two-yearly KL-6 measurements: Δ1(t1-t0), Δ2(t2-t1) and Δ3(t3-t2). In SSc-ILD patients with PPFE pattern, Δ3 was significantly different than those without PPFE pattern (P = .0020). Serum KL-6 levels were significantly different (P = .0455) either at Δ2 and Δ3 in the PPFE group. In SSc-ILD patients with PPFE, at t3 serum KL-6 concentrations were inversely correlated with FEV1 (r = -.76; P = .037) and FVC percentages (r = -.79; P = .028).

Conclusion: These results suggest that serial measurements of KL-6 in the follow-up of these patients may help to monitor disease progression. In real life, in SSc-ILD patients PPFE should be always evaluated at CT and when present should suggest a tight follow-up to monitor its evolution.
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http://dx.doi.org/10.1111/eci.13543DOI Listing
March 2021

Effectiveness of SB5, an Adalimumab Biosimilar, in Patients With Noninfectious Uveitis: A Real-Life Monocentric Experience.

Asia Pac J Ophthalmol (Phila) 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, University of Siena, Siena, Italy Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy Department of Medicine, Ophthalmology Unit, Surgery and Neuroscience, University of Siena, Siena, Italy Pharmacy Unit, Siena University Hospital 'Santa Maria alle Scotte', Siena, Italy.

Purpose: Several concerns have arisen with biosimilars in terms of immunogenicity, safety issues, loss of efficacy, and extrapolation to other indications. The study aim was to evaluate the efficacy of SB5, an adalimumab biosimilar, in noninfectious uveitis (NIU).

Design: Retrospective nonrandomized study.

Methods: Data from patients with refractory NIU treated with SB5 (Imraldi, Biogen) were analyzed at baseline, 3 months after SB5 initiation and at the last follow-up in terms of uveitis relapses, occurrence of retinal vasculitis, resolution of uveitic macular edema (UME), best-corrected visual acuity, glucocorticoids (GCs)-sparing effect and drug survival.

Results: Uveitis relapses decreased from 121 relapses/100 patients/year in the 12 months before SB5 initiation to 4 relapses/100 patients/year during the first 12 months of treatment (P = 0.0004). Uveitis was inactive in 46/47 eyes at the end of the study period. The number of eyes with active retinal vasculitis decreased during the study period (P < 0.0001). At baseline, 6 eyes presented UME, whereas no eye had UME at the last follow-up. Mean best-corrected visual acuity increased from 7.7 ± 3.41 at baseline to 8.9 ± 2.46 at the last follow-up (P = 0.0045). Mean GCs daily dosage decreased from 18.33 ± 10.33 mg at baseline to 5.75 ± 2.29 mg at the last follow-up (P = 0.018). The cumulative SB5 retention rate was 91.8% at both 12- and 20-month follow-up.

Conclusions: SB5 biosimilar is effective in NIU by drastically reducing uveitis relapses and the occurrence of retinal vasculitis. Moreover, SB5 biosimilar improved visual acuity, allowed a significant GCs-sparing effect and showed an excellent drug retention rate.
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http://dx.doi.org/10.1097/APO.0000000000000380DOI Listing
March 2021

Difference in pain and accuracy of two hyaluronic acid injection techniques for symptomatic knee osteoarthritis in overweight patients.

Reumatologia 2021 28;59(1):23-26. Epub 2021 Feb 28.

Department of Medicine, Surgery and Neurosciences, Rheumatology Unit, University of Siena, Italy.

Objectives: To evaluate differences of injection related pain, and the accuracy of the techniques in two groups of overweight patients, performing the anterolateral approach for one group (G1) and the superolateral approach for the second group (G2).

Material And Methods: In the study, 126 knee joints from 86 osteoarthritis (OA) patients were evaluated. Inclusion criteria were body mass index (BMI) ≥ 25, absence of effusion and coagulopathy. Pain evaluation during injection was evaluated with Visual Analogue Scale (VAS), while accuracy of the procedure was evaluated with ultrasound (US).

Results: The patients' mean age was 69.9 ±9.01, VAS for G1 group was 1.71 ±1.89, for G2 group was 1.74 ±1.31. Mean BMI was 29.69 ±2.86, for G1 group was 28.29 ±3.29, for G2 group was 30.32 ±2.41. No adverse events (AE) occurred in both studied groups. The accuracy rate of the procedure was 69.1% for G1 (38/55 knees), 95.7% for G2 (68/71 knees). No significant difference was found in VAS pain score between G1 and G2 group ( = 0.45). We found the significant correlation between BMI and VAS pain score in anterolateral accesses (G1) ( = 0.51; < 0.005). No correlation was found between age and VAS pain score in anterolateral access (G1). For the superolateral access (G2), no correlation was found for age or BMI and VAS pain score.

Conclusions: Hyaluronic acid injection is safe therapeutic option for knee OA with no significant differences between anterolateral and superolateral approaches in terms of pain in overweight patients. However, higher BMI seems to be a predictor of pain in anterolateral access, and the superolateral approach should be preferred in this group of patients.
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http://dx.doi.org/10.5114/reum.2021.103646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944963PMC
February 2021

Diffuse Peripheral Enthesitis in Metabolic Syndrome: A Retrospective Clinical and Power Doppler Ultrasound Study.

Reumatol Clin 2021 Feb 24. Epub 2021 Feb 24.

Rheumatology Unit, University of Siena, Santa Maria alle Scotte Hospital, Siena, Italy.

Objectives: To investigate peripheral enthesitis with power Doppler ultrasound (PDUS) in patients presenting low back pain (LBP) and metabolic syndrome (MetS) in comparison with patients with only LBP, to correlate US scores with clinical-anthropometric characteristics, and to define any relationship between enthesitis and concurrent diffuse idiopathic hyperostosis syndrome (DISH).

Methods: Sixty outpatients with LBP and MetS, evaluated with multi-site entheseal PDUS, scoring inflammatory and structural damage changes, were retrospectively analyzed. A group of 60 subjects with LBP, without MetS and evaluated with the same protocol, was analyzed as the control group.

Results: Patients showed overweight (BMI 29.8) and low-grade inflammatory state (C-reactive protein [CRP] 0.58mg/dL, erythrosedimentation rate [ESR] 20.2mm/h). Enthesitis was demonstrated in 52 (86%) patients (17.6% entheses), and in 8 controls (13.3%) (p<.00001). PD signals (15% of patients) were associated with entheseal pain (p=.0138). US scores correlated with body mass index (BMI), pain, type 2 diabetes. In 28 (46%) patients a concurrent DISH was diagnosed, correlating with older age (p<.0001), CRP (p=.0428), ESR (p=.0069) and PDUS scores (p=.0312 inflammatory, p=.0071 structural). MetS had a strong association (OR 4.375, p=.0007) with concurrent DISH.

Conclusions: Diffuse peripheral enthesitis is very common in MetS. Almost half of MetS patients can have a concurrent diagnosis of DISH; they are older, with higher inflammation, and higher PDUS enthesitis scores.
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http://dx.doi.org/10.1016/j.reuma.2020.12.005DOI Listing
February 2021

Resolution of Schnitzler's syndrome after haematopoietic stem cell transplantation.

Clin Exp Rheumatol 2021 Feb 26. Epub 2021 Feb 26.

Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy.

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February 2021

Pleuroparenchymal fibroelastosis in interstitial lung disease with antineutrophil cytoplasmic antibody-associated vasculitis.

Clin Exp Rheumatol 2021 02 25. Epub 2021 Feb 25.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

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February 2021

Biologic drugs in the treatment of polyarteritis nodosa and deficit of adenosine deaminase 2: A narrative review.

Autoimmun Rev 2021 Apr 17;20(4):102784. Epub 2021 Feb 17.

Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy. Electronic address:

Polyarteritis nodosa (PAN) is a medium vessels vasculitis variously involving different organs and systems, sometimes with an aggressive course, leading to death or disability in a significant number of cases. First-line treatment usually relies on steroids and classical immunosuppressants, but a growing number of case reports and small case series shows the potential role of biologic drugs, mostly anti-tumor necrosis factor (TNF)-α agents, in inducing and maintaining remission in patients affected by PAN. Similarly, the recently described autoinflammatory disease named deficit of adenosine deaminase 2 (DADA2), considered by several experts as a more precocious and aggressive variant of PAN, seems to respond to a prompt treatment with TNF-α inhibitors. The aim of this review is to collect all existing evidences about the use of biologic drugs in PAN and DADA2. Fifty-one articles published during the last 15 years were retrieved, including 58 and 76 patients affected by PAN and DADA2, respectively, and treated with biologic drugs. The majority of subjects was treated with TNF-α inhibitors, whose effectiveness was reported in the treatment of such difficult-to-manage diseases, particularly in DADA2. Among the other biologic drugs, Tocilizumab was successfully employed in some subjects affected by PAN who did not respond to TNF-α inhibitors, while Rituximab did not give substantial benefits neither in PAN nor in DADA2. Only few data exist about the role of Janus-kinase inhibitors and anti-IL1 agents. This study provides the first comprehensive assessment of biologic agents in both PAN and DADA2, with encouraging results especially in the context of TNF-α inhibitors. Nevertheless, due to the lack of prospective, randomized, case control studies, further efforts should be made in order to fully elucidate the role of these drugs in such rare and life-threatening conditions.
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http://dx.doi.org/10.1016/j.autrev.2021.102784DOI Listing
April 2021

Epidemiology of systemic sclerosis: a multi-database population-based study in Tuscany (Italy).

Orphanet J Rare Dis 2021 02 17;16(1):90. Epub 2021 Feb 17.

Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, Pisa, Italy.

Background: Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions.

Results: The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6-37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17-2.35), congestive heart failure (HR = 2.76, CI 95% 1.80-4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21-4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06-2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008-2017 period.

Conclusions: The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.
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http://dx.doi.org/10.1186/s13023-021-01733-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890847PMC
February 2021

NEUTROPHIL EXTRACELLULAR TRAPS RELEASE IN GOUT AND PSEUDOGOUT DEPENDS ON THE NUMBER OF CRYSTALS REGARDLESS OF LEUKOCYTE COUNT.

Rheumatology (Oxford) 2021 Jan 30. Epub 2021 Jan 30.

Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, Policlinico Santa Maria alle Scotte, Siena, Italy.

Objectives: Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in synovial fluid. Recently, the production of neutrophil extracellular traps (NETs) embedding monosodium urate crystals (MSU) has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in synovial fluids during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyze activation of necroptosis pathway in synovial fluid from crystal-induced arthritis.

Methods: Synovial fluid samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in synovial fluid by nucleic acid stain and by quantification of human neutrophil elastase. Activation of p-MLKL was assessed by western blot.

Results: We observed that synovial fluid neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in synovial fluid and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway.

Conclusions: Our findings suggest that a role of NETs in crystal-induced arthritis is to "trap extracellular particles", including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition and may have implications for disease evolution, rather than for spontaneous resolution of the acute attack.
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http://dx.doi.org/10.1093/rheumatology/keab087DOI Listing
January 2021

Efficacy and safety of baricitinib in 446 patients with rheumatoid arthritis: a real-life multicentre study.

Clin Exp Rheumatol 2020 Dec 18. Epub 2020 Dec 18.

Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, and Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy.

Objectives: Baricitinib, an oral Janus kinase (JAK) 1-2 inhibitor, is currently used along biologic DMARDs (bDMARDs) after the failure of methotrexate (MTX) in rheumatoid arthritis (RA). We investigated the efficacy and safety of baricitinib in real life.

Methods: We prospectively enrolled 446 RA patients treated with baricitinib from 11 Italian centres. Patients were evaluated at baseline and after 3, 6, and 12 months. They were arrayed based on previous treatments as bDMARD-naïve and bDMARD-insufficient responders (IR) after the failure or intolerance to bDMARDs. A sub-analysis differentiated the effects of methotrexate (MTX) and the use of oral glucocorticoids (OGC).

Results: Our cohort included 150 (34%) bDMARD-naïve and 296 (66%) bDMARD-IR patients, with 217 (49%) using baricitinib as monotherapy. Considering DAS-28-CRP as the primary outcome, at 3 and 6 months, 114/314 (36%) and 149/289 (51.6%) patients achieved remission, while those in low disease activity (LDA) were 62/314 (20%) and 46/289 (15.9%), respectively; finally at 12 months 81/126 (64%) were in remission and 21/126 (17%) in LDA. At all-timepoints up to 12 months, bDMARDs-naïve patients demonstrated a better clinical response, independently of MTX. A significant reduction in the OGC dose was observed at 3 and 12 months in all groups. The serum positivity for both rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA) conferred a lower risk of stopping baricitinib due to inefficacy. Fifty-eight (13%) patients discontinued baricitinib due to adverse events, including thrombotic events and herpes zoster reactivation.

Conclusions: Real-life data confirm the efficacy and safety profiles of baricitinib in patients with RA and provide evidence that drug survival is higher in bDMARDs-naïve and seropositive patients.
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December 2020

The switch from etanercept originator to SB4: data from a real-life experience on tolerability and persistence on treatment in joint inflammatory diseases.

Ther Adv Musculoskelet Dis 2020 13;12:1759720X20964031. Epub 2020 Oct 13.

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

Aims: Switching from originator to biosimilar is part of current practice in inflammatory rheumatic musculoskeletal diseases (iRMDs) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA), with evidences derived from both etanercept (ETN) to SB4-switching randomized controlled trials and real-life registries. We investigated the safety and treatment persistence of ETN/SB4 in a multi-iRMD cohort derived from two rheumatology departments in our region.

Methods: Adult patients with iRMDs, treated with ETN for at least 6 months and switched to SB4 in stable clinical condition, were eligible for this retrospective evaluation. Retrospective data on adverse events, loss of efficacy and persistence on treatment were collected until latest available follow-up.

Results: A total of 220 patients (85 RA, 81 PsA, 33 axSpA, 14 juvenile idiopathic arthritis and seven other conditions; 142 females, mean age 58 ± 7 years, disease duration 12 ± 4 years, ETN duration 7 ± 4 years) were enrolled, with median follow-up of 12.1 (9.7-15.8) months. A total of 50 patients (22.7%) presented with at least one adverse event, with 36 (16.4%) disease flares and 30 (13.6%: 11 for safety and 19 loss of efficacy) SB4 withdrawals. Cumulative SB4 treatment persistence was 99.1%, 88.6% and 64.6% at 6, 12 and 18 months respectively. Back-switch to ETN was performed in 17/30 cases, the remaining cases were managed with change of biologic disease modifying or conventional synthetic anti-rheumatic drug. Age was the only significant predictor of SB4 interruption at 6 months.

Conclusion: Our real-life data confirm the safety profile of switching from ETN to SB4, with slightly higher treatment persistence rates compared with other real-life registries.
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http://dx.doi.org/10.1177/1759720X20964031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576915PMC
October 2020

Real-Life Data on the Efficacy of Canakinumab in Patients with Adult-Onset Still's Disease.

Mediators Inflamm 2020 15;2020:8054961. Epub 2020 Oct 15.

Research Center of Systemic Autoinflammatory Diseases, Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Background: Interleukin-1 inhibition has revealed to be a successful treatment approach for patients with adult-onset Still's disease (AOSD). However, real-life experience is focused on the use of anakinra, while data about canakinumab (CAN) are mainly based on case reports and small case series. . Patients classified with AOSD according to Yamaguchi criteria and treated with CAN were consecutively enrolled. Their clinical and therapeutic data were retrospectively collected and statistically analysed to assess the role of CAN as a therapeutic opportunity in AOSD patients in terms of clinical and laboratory disease control along with corticosteroid-sparing effect.

Results: Nine AOSD patients (8 females and 1 male) treated with CAN for 15.00 ± 12.3 months were enrolled. Resolution of clinical manifestations was reported in 8/9 cases at the 3-month assessment; a significant decrease in the number of tender joints ( = 0.009), swollen joints ( = 0.027), and disease activity score on 28 joints-C-reactive protein (DAS28-CRP) ( = 0.044) was observed during the study period. The systemic score of disease activity significantly decreased at the 3-month and 6-month assessments and at the last visit compared to the start of treatment ( = 0.028, = 0.028, and = 0.018, respectively). The daily corticosteroid dosage was significantly reduced at the 3-month and at the last follow-up visits ( = 0.017 and = 0.018, respectively). None of the patients experienced adverse events or severe adverse events during the follow-up.

Conclusions: CAN has shown prompt and remarkable effectiveness in controlling AOSD activity in a real-life contest, with a significant glucocorticoid-sparing effect and an excellent safety profile.
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http://dx.doi.org/10.1155/2020/8054961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584965PMC
October 2020

The Technique of Intradiscal Injection: A Narrative Review.

Ther Clin Risk Manag 2020 9;16:953-968. Epub 2020 Oct 9.

Physical and Rehabilitation Medicine, University of Rome "Tor Vergata", Rome, Italy.

Background: Low back pain (LBP) is one of the most common spine diseases and represents the most frequent cause of absence from work in developed countries. Approximately 40% of chronic LBP is related to discogenic origin. The goal of the study is producing a review of literature to describe analytically the techniques of intradiscal injections.

Methods: PubMed database was searched for clinical studies with the different key terms: "intradiscal", "injection", "steroid" "procedures", "techniques", "CT", "MRI", "fluoroscopy", "fluoroscopic", "guidance", "ozone", "ultrasound", "images". Only studies written in English, French, or Italian in which the intradiscal injection represents the main procedure for the low back discopathy treatment on humans were considered. We excluded the articles that do not mention this procedure; those which indicated that the intradiscal injection had happened accidentally during other treatments; those reporting the patient's pain was determined by other causes than the discopathy (facet joint syndrome, tumor, spondylodiscitis).

Results: Thirty-one articles dated from 1969 to 2018 met the criteria. The examined population was 6843 subjects, 52.3% male and 47.7% female, with a mean age of 45.9±10.1 years. The techniques are highly variable in terms of procedure: different operators, needle guidance, injection sites, drugs, tilt angle of the needle).

Conclusion: The efficacy and the safety of the intradiscal procedures are not easily comparable due to different types of studies and their limited number. Further studies are needed to standardize the intradiscal injection technique/procedure to improve safety, repeatability and effectiveness, and last but not least to reduce peri- and postoperative care and health-care costs.
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http://dx.doi.org/10.2147/TCRM.S251495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553660PMC
October 2020

Sonozaki syndrome in the spotlight of imaging.

Clin Rheumatol 2021 Mar 22;40(3):1193-1194. Epub 2020 Oct 22.

Unit of Diagnostic Imaging, Department of Medical, Surgical and Neuro Sciences and of Radiological Sciences, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.

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http://dx.doi.org/10.1007/s10067-020-05472-yDOI Listing
March 2021

Portable Pocket-Sized Ultrasound Scanner for the Evaluation of Lung Involvement in Coronavirus Disease 2019 Patients.

Ultrasound Med Biol 2021 01 21;47(1):19-24. Epub 2020 Sep 21.

Respiratory Diseases Unit, Department of Medical Sciences, University Hospital of Siena (Azienda Ospedaliera Universitaria Senese, AOUS), Siena, Italy; Department of Medical, Surgical and Neurological Sciences, University of Siena, Italy.

Ultrasound imaging of the lung (LUS) and associated tissues has demonstrated clinical utility in coronavirus disease 2019 (COVID-19) patients. The aim of the present study was to evaluate the possibilities of a portable pocket-sized ultrasound scanner in the evaluation of lung involvement in patients with COVID-19 pneumonia. We conducted 437 paired readings in 34 LUS evaluations of hospitalized individuals with COVID-19. The LUS scans were performed on the same day with a standard high-end ultrasound scanner (Venue GO, GE Healthcare, Chicago, IL, USA) and a pocket-sized ultrasound scanner (Butterfly iQ, Butterfly Network Inc., Guilford, CT, USA). Fourteen scans were performed on individuals with severe cases, 11 on individuals with moderate cases and nine on individuals with mild cases. No difference was observed between groups in days since onset of symptoms (23.29 ± 10.07, 22.91 ± 8.91 and 28.56 ± 11.13 d, respectively; p = 0.38). No significant differences were found between LUS scores obtained with the high-end and the portable pocket-sized ultrasound scanner. LUS scores in individuals with mild respiratory impairment were significantly lower than in those with moderate and severe cases. Our study confirms the possibilities of portable pocket-sized ultrasound imaging of the lung in COVID-19 patients. Portable pocket-sized ultrasound scanners are cheap, easy to handle and equivalent to standard scanners for non-invasive assessment of severity and dynamic observation of lung lesions in COVID-19 patients.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505580PMC
January 2021

SARS-CoV-2 in pleural fluid in a kidney transplant patient.

Postgrad Med 2020 Oct 27:1-4. Epub 2020 Oct 27.

Department of Medical, Surgical and Neurological Sciences, University of Siena, Italy.

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread all over the globe from China. Pleural involvement is not common; around 5-10% of patients can develop pleural effusion and little is known about the involvement of pleural structures in this new infection.A 61-year-old male kidney transplant patient with a history of multiple biopsy-confirmed acute rejections and chronic allograft rejection was admitted to our COVID-19 Unit with dry cough, exertional dyspnea, oliguria, and abdominal distension. Lung ultrasound imaging, chest X-ray, and CT scan showed left pleural effusion and atelectasis of the neighboring lung parenchyma. RT-PCR was positive for SARS-CoV-2 in the pleural fluid and cytology showed mesothelial cells with large and multiple nuclei, consistent with a cytopathic effect of the virus.This is one of few reports describing detection of SARS-CoV-2 in the pleural fluid and to the best of our knowledge, is the first to document the simultaneous presence of a direct cytopathic effect of the virus on mesothelial cells in a kidney transplant patient with COVID-19 pneumonia. The pleura proved to be a site of viral replication where signs of a direct pathological effect of the virus on cells can be observed, as we report here. RT-PCR for SARS-CoV-2 should be part of routine examination of pleural effusion even in patients with mild respiratory symptoms or with comorbidities that seem to explain the cause of effusion.
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http://dx.doi.org/10.1080/00325481.2020.1838817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605650PMC
October 2020

The Role of Multimodality Imaging in Monitoring Disease Activity and Therapeutic Response to Tocilizumab in Giant Cell Arteritis.

Mediators Inflamm 2020 27;2020:3203241. Epub 2020 Sep 27.

Department of Medicine, Surgery and Neurosciences, Rheumatology Unit, University of Siena, Italy.

Introduction: Giant cell arteritis (GCA) is a large vessel (LV) vasculitis, mainly affecting elder patients. Monitoring GCA activity during tocilizumab (TCZ) treatment is an unmet need, since low serum levels of C-reactive protein (CRP) during treatment may underestimate disease activity. To date, few data are available on the role of different imaging techniques in monitoring GCA activity and response to treatment. We report herein a cohort of GCA patients treated with TCZ and followed up with multimodal imaging. . We collected clinical, laboratory, and imaging data of 11 GCA patients treated with TCZ 162 mg subcutaneously every week. Disease activity was assessed at baseline and within 12 months from the start of treatment using different imaging techniques such as color Doppler ultrasonography (CDUS), magnetic resonance imaging/angiography (MRI/MRA), computed tomography angiography (CTA), and/or positron emission tomography (PET).

Results: Four patients were affected by cranial and 7 by LV-GCA. All patients were treated with oral glucocorticoids (GCs) (mean dose 55.68 mg ± 8.19 of prednisone or equivalent) in combination with TCZ. Treatment was preceded in 5 cases by 3 intravenous boluses of 1000 mg methylprednisolone. A significant decrease of the mean dose of oral GCs was observed between baseline and the last follow-up visit (4.65 ± 3.69 mg) ( = 0.003). TCZ treatment significantly decreased erythrocyte sedimentation rate ( < 0.01) and CRP levels ( < 0.01). At follow-up (mean 8.18 ± 3.63 months), all patients were in clinical and serological remission. Moreover, PET, CDUS, MRI/MRA, and CTA did not show any LVV finding.

Conclusions: Our study highlights TCZ efficacy in inducing GCA remission and its steroid-sparing effect. We highlighted a reliability of imaging procedures in the evaluation of disease activity and treatment response. A close disease monitoring with imaging techniques should be taken into account in GCA patients during TCZ treatment.
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http://dx.doi.org/10.1155/2020/3203241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537685PMC
September 2020

Sézary syndrome during anti-IL17 treatment.

Dermatol Ther 2020 11 28;33(6):e14321. Epub 2020 Sep 28.

Dermatology Section, Department of Medical, Surgical, and Neurological Sciences, Santa Maria Alle Scotte Hospital, Siena, Italy.

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http://dx.doi.org/10.1111/dth.14321DOI Listing
November 2020

Anterior chest wall non-traumatic diseases: a road map for the radiologist.

Acta Biomed 2020 07 13;91(8-S):43-50. Epub 2020 Jul 13.

Unit of Diagnostic Imaging, Department of Medical, Surgical and Neuro Sciences and of Radiological Sciences, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.

The anterior chest wall (AWC) non-traumatic pathologies are largely underestimated, and early detection through imaging is becoming increasingly important. This paper aims to review the major non-traumatic ACW pathologies, with a particular interest in imaging features and differential diagnosis.
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http://dx.doi.org/10.23750/abm.v91i8-S.9972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944680PMC
July 2020

Power and spectral Doppler ultrasound in suspected active sacroiliitis: a comparison with magnetic resonance imaging as gold standard.

Rheumatology (Oxford) 2021 Mar;60(3):1338-1345

Department of Medical, Surgical and Neurosciences, Rheumatology Unit, Arezzo, Italy.

Objectives: The objectives of this study were to study with Power Doppler US (PDUS) the SI joints (SIJs) of patients with suspected active sacroiliitis, to describe SIJ flows with spectral wave analysis (SWA) on Doppler US, and to correlate US data with both clinical characteristics and presence of SIJ bone marrow oedema (BME) in subsequent MRI.

Methods: A total of 42 patients (32 females and 10 males, mean age 46.8 years) with recent onset of inflammatory back pain (IBP) were included. Every patient underwent US examination with a convex 1-8 MHz probe [scoring PDUS signals with a three-point scale and describing flows in SWA calculating the mean Resistive Index (RI)] and subsequent MRI of the SIJs.

Results: PDUS signals were detected in 34 patients and 62 SIJs. In 29 patients and 56 SIJs, MRI revealed BME. A definite diagnosis of SpA was made in 32 patients. PDUS signals were more frequent (P < 0.0001) in patients with a final diagnosis of SpA, yielding a higher PDUS score (P = 0.0304). PDUS grading correlated with both BME grading (r = 0.740, P = 0.0001) and AS DAS (ASDAS) (r = 0.6257, P = 0.0004), but not with inflammatory reactants nor anthropometric data. Mean RI were, respectively, 0.60 and 0.73 (P < 0.0001) in patients with or without diagnosis of active sacroiliitis. The most inclusive RI cut-off resulted <0.70 [positive predictive value (PPV) 94%, accuracy 90%, P = 0.0001]. The best Likelihood Ratio (5.471) for RI to detect pathologic cases was obtained with a cut-off of <0.60 (PPV 96%).

Conclusions: PDUS and SWA of SIJs demonstrate good diagnostic accuracy for active sacroiliitis compared with MRI.
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http://dx.doi.org/10.1093/rheumatology/keaa546DOI Listing
March 2021

Ruxolitinib Rapidly Reduces Acute Respiratory Distress Syndrome in COVID-19 Disease. Analysis of Data Collection From RESPIRE Protocol.

Front Med (Lausanne) 2020 4;7:466. Epub 2020 Aug 4.

Hematology Unit, Università of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.

The Coronavirus disease (COVID-19) pandemic is causing millions of infections and hundreds of thousands of deaths worldwide. Cumulative clinical and laboratory evidence suggest that a subset of patients with severe COVID-19 may develop a cytokine storm syndrome during the course of the disease, with severe respiratory impairment requiring ventilatory support. One field of research nowadays is to identify and treat viral-induced hyperinflammation with drugs used in other clinical conditions characterized by an hyperinflammation status. These drugs might help to reduce COVID19 mortality. Ruxolitinib, a JAK1 and JAK2 inhibitor, has been successfully used to treat severe immune-mediated diseases, such as graft vs. host disease and Hemophagocytic lymphohistiocytosis. We used ruxolitinib in 18 patients with clinically progressive COVID-19 related acute respiratory distress syndrome, with a primary endpoint to rapidly reduce the degree of respiratory impairment and as a secondary endpoint to rapidly restore the PaO/FiO ratio, as an evaluation of clinical status, and monitoring of drug related Adverse Events. Parameters of inflammation responses and organ functions were assessed and monitored. The treatment plan was ruxolitinib 20 mg bid for the first 48 h and subsequent two-step de-escalation at 10 mg bid and 5 mg bid for a maximum of 14 days of treatment. Our data collection shows a rapid clinical response with no evolution from to mechanical ventilation in 16/18 patients and no response in two patients (overall response rate-ORR 89%). Already after 48 h of ruxolitinib treatment 16/18 patients showed evident clinical improvement, and after 7 days of treatment 11/18 patients showed fully recovered respiratory function (pO > 98% in spontaneous breathing), 4/18 patients had minimal oxygen requirement (2-4 L/m), 1/18 patient showed stable disease, and 2/18 patient showed progressive disease. After 14 days, 16/18 patients showed complete recovery of respiratory function (ORR 89%). Compliance to ruxolitinib planned treatment was 100% and no serious adverse event was recorded. In our case series of 18 critically ill patients with COVID-19 and ARDS, administration of ruxolitinib resulted in a clinical improvement that concurred to modify the standard course of disease. Ruxolitinib can be a therapeutic option for patients with respiratory insufficiency in COVID-19 related ARDS. RESPIRE Study (uxolitinib for the treatment of acute rratory distss syndrome, ClinicalTrials.gov Identifier: NCT04361903).
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http://dx.doi.org/10.3389/fmed.2020.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417512PMC
August 2020

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF- Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.

Mediators Inflamm 2020 7;2020:8562485. Epub 2020 Aug 7.

Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients' data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group ( < 0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with < 0.01 and < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults ( < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations ( < 0.01), while oral aphthosis was more frequently found in the LP variant group ( < 0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values ( < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods ( < 0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria ( < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group ( < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients ( < 0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype ( < 0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.
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http://dx.doi.org/10.1155/2020/8562485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428902PMC
August 2020