Impact of age and cardiovascular risk factors on the incidence of adverse events in patients with rheumatoid arthritis treated with Janus Kinase inhibitors: data from a real-life multicentric cohort.

Inhibiting Janus Kinases (JAK) is a crucial therapeutic strategy in rheumatoid arthritis (RA). However, the use of JAK inhibitors has recently raised serious safety concerns. The study aims to evaluate the safety profile of JAKi in patients with RA and identify potential risk factors (RFs) for adverse events (AEs). Data of RA patients treated with JAKi in three Italian centers from January 2017 to December 2022 were retrospectively analyzed. 182 subjects (F:117, 64.3%) underwent 193 treatment courses. 78.6% had at least one RF, including age ≥ 65 years, obesity, smoking habit, hypertension, dyslipidemia, hyperuricemia, diabetes, previous VTE or cancer, and severe mobility impairment. We identified 70 AEs (28/100 patients/year), among which 15 were serious (6/100 patients/year). A high disease activity was associated with AEs occurrence (p = 0.03 for CDAI at T0 and T6; p = 0.04 for SDAI at T0 and T6; p = 0.01 and p = 0.04 for DAS28ESR at T6 and T12, respectively). No significant differences in AEs occurrence were observed after stratification by JAKi molecules (p = 0.44), age groups (p = 0.08) nor presence of RFs (p > 0.05 for all of them). Neither the presence of any RFs, nor the cumulative number of RFs shown by the patient, nor age ≥ 65 did predict AEs occurrence. Although limited by the small sample size and the limited number of cardiovascular events, our data do not support the correlation between cardiovascular RFs-including age-and a higher incidence of AEs during JAKi therapy. The role of uncontrolled disease activity in AEs occurrence should by emphasized.

Diagnostic accuracy of OGUS, Southend halo score and halo count in giant cell arteritis.

Objectives: Ultrasound has a paramount role in the diagnostic assessment of giant cell arteritis (GCA); Southend halo score (HS), halo count (HC), and OMERACT GCA Ultrasonography Score (OGUS) are the first quantitative scores proposed in this setting. The aim of this study was therefore to assess the diagnostic accuracy of these scores in a real-life scenario, as well as to evaluate their optimal cutoff, also with respect to disease extent, sex, and age. Methods: We retrospectively collected clinical, serological, and US findings of all patients referred for the first time to our vasculitis clinic in the suspicion of GCA. Results: A total of 79 patients were included, and a definite diagnosis of GCA was made in 43 patients. For OGUS, the ROC curve showed an optimal cut point of 0.81 (sensitivity 79.07% and specificity 97.22%). For HC and HS, the optimal cutoff values were > 1.5 (sensitivity 76.7% and specificity 97.2%) and > 14.5 (sensitivity 74.4% and specificity 97.2%), respectively. No relevant differences were assessed when patients were stratified according to disease extent, age, and sex. Compression sign (CS) was positive in 34 of 38 patients with cranial GCA and negative in all controls and LV-GCA. Conclusion: All three scores display good sensitivity and excellent specificity, although the cutoff was slightly different than proposed. In particular, for OGUS, a threshold of 0.81 could be employed for diagnostic purposes, although it was developed solely for monitoring. Due to its high sensitivity and specificity, CS should be always assessed in all patients referred with a suspicion of cranial GCA.

The Role of Major Salivary Gland Ultrasound in the Diagnostic Workup of Sicca Syndrome: A Large Single-Centre Study.

(1) Objective: To determine the diagnostic accuracy of major salivary gland ultrasonography (SGUS) in primary Sjogren's syndrome (SS), we used the Outcome Measures in Rheumatology Clinical Trials (OMERACT) scoring system on a large single-centre cohort of patients with sicca syndrome. (2) Method: We retrospectively collected the clinical, imaging and serological data of all the patients referred with a suspicion of SS who underwent SGUS and minor salivary glands biopsy. (3) Results: A total of 132 patients were included. The SGUS scores were correlated between the two sides (p < 0.001). The diagnostic cut-off for SS (AUROC: 0.7408) was 6 for the SGUS-global sum (sensitivity: 32.43%; specificity: 96.84%). The cut-off with the highest specificity for SS diagnosis was 7. In the patients with a final diagnosis of SS, the mean SGUS score was significantly higher (p < 0.001) than that of the non-SS patients (3.73 vs. 1.32 for the SGUS-global sum). A significant correlation was demonstrated between the SGUS scores and final SS diagnosis (p < 0.001), biopsy positivity (p < 0.001), ANA positivity (p = 0.016), Ro-SSA positivity (p = 0.01), and gland fibrosis (p = 0.02). (4) Conclusions: SGUS, using the OMERACT scoring system, has moderate sensitivity and high specificity for the diagnosis of SS. The scoring showed a strong and direct correlation with all the clinical hallmarks of SS diagnosis, such as the positivity of a labial salivary gland biopsy, ANA and Ro-SSA statuses, and salivary gland fibrosis. Because of its high specificity, a SGUS-global score > 6 could be therefore employed for the diagnosis of SS in the case of ANA negativity or the unavailability of a biopsy.

ToRaRI (Tofacitinib in Rheumatoid Arthritis a Real-Life experience in Italy): Effectiveness, safety profile of tofacitinib and concordance between patient-reported outcomes and physician's global assessment of disease activity in a retrospective study in Central-Italy.

INTRODUCTION: The use of Janus Kinase Inhibitors (JAK-Is) in rheumatoid arthritis (RA) has entered in daily practice. In consideration of ORAL-Surveillance trial and the new EULAR recommendations, real-world data are needed to assess Jak-Is safety and effectiveness. The multicenter study presented here aimed to evaluate effectiveness and safety of tofacitinib in a real-life cohort. METHODS: A retrospective analysis was performed from September 2021 to December 2022. Data were collected when tofacitinib was started (T0) and after 3 (T3), 6 (T6) and 12 (T12) months of treatment. The primary objective was to analyze the efficacy and safety of tofacitinib. Safety was assessed by recording adverse events (AEs) with and without discontinuation. The secondary objective was to assess the difference between Patient-Reported Outcomes (PROs) and Physician's Global Assessment of disease activity (PhGA). RESULTS: 122 patients were included in the study from the following rheumatology Centers: Pisa, Ancona, Florence (two Centers), Siena, and Sardinia. A statistically significant improvement in DAS-28-CRP, CDAI and SDAI score was observed at T3, T6, compared to baseline (p < 0.001). Improvement was confirmed in patients who reach T12. Patients naïve to bDMARDs showed a shorter remission time and higher remission rates. There was also a statistically significant improvement in PROs compared to baseline (p < 0.001). The improvement was rapid and was consistent with PhGA. The 12-month retention rate for tofacitinib was 89.35%. Reasons to stop tofacitinib were: insufficient response (7), gastrointestinal symptoms (2), infection (1), malignancy (1), Zoster (1), pruritus sine materia (1). CONCLUSIONS: Tofacitinib is safe and effective in our RA cohort. It induces higher remission rates in patients naive to bDMARDs, suggesting that there may be a benefit using it as first-line therapy. Additionally, improvement in PROs was consistent with PhGA scores, demonstrating how tofacitinib affects both the objective and subjective components of disease activity. Key Points 1. JAK inhibitors are considered at a similar level as biologic agents in terms of effectiveness. 2. After ORAL-Surveillance results, real-world data are needed to assess the benefit/risk profile of Jaki. 3. Disagreement between patients and physicians has been previously reported with biologic therapy among patients with rheumatoid arthritis, with patients rating disease activity higher than physicians. 4. Jak inhibitors could reduce this discrepancy, due to their mechanism of action.

ReLiFiRa (Real Life Filgotinib in Rheumatoid Arthritis): Retrospective Study of Efficacy and Safety in Common Clinical Practice.

BACKGROUND: Filgotinib (FIL) is a selective JAK1 inhibitor with an affinity 30-fold higher than JAK2, approved to treat moderate to severe active rheumatoid arthritis (RA), in adults with inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). METHODS: We conducted a retrospective, multicentric study in order to evaluate efficacy and safety of FIL 200 mg daily therapy, after 3 and 6 months, in 120 patients affected by RA, managed in Tuscany and Umbria rheumatological centers. The following clinical records were analyzed: demographical data, smoking status, previous presence of comorbidities (Herpes zoster -HZ- infection, venous thromboembolism -VTE-, major adverse cardiovascular events -MACE-, cancer, diabetes, and hypertension), disease duration, presence of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), number of biological failures, and prior csDMARDs utilized. At baseline, and after 3 (T3) and 6 (T6) months of FIL therapy, we evaluated mean steroid dosage, csDMARDs intake, clinimetric indexes (DAS28, CDAI, HAQ, patient and doctor PGA, VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and body mass index (BMI). RESULTS: At baseline, the mean disease duration was 9.4 ± 7.5 years; the prevalence of previous HZ infection, VTE, MACE, and cancer was respectively 4.12%, 0%, 7.21%, and 0.83%, respectively. In total, 76.3% of patients failed one or more biologics (one biological failure, 20.6%; two biological failures, 27.8%; three biological failures, 16.5%; four biological failures, 10.3%; five biological failures, 1.1%). After 3 months of FIL therapy, all clinimetric index results significantly improved from baseline, as well as after 6 months. Also, ESR and CRP significatively decreased at T3 and T6. Two cases of HZ were recorded, while no new MACE, VTE, or cancer were recorded during the observation time. CONCLUSION: Despite the limitations of the retrospective study and of the observational period of only 6 months, real-life data on the treatment of RA patients with FIL demonstrate that this Jak inhibitor therapy is safe in terms of CV, VTE events, and occurrence of cancer, and is also effective in a population identified as "difficult to treat" due to failure of previous b-DMARD therapy.

Baricitinib retention rate: 'real-life' data from a mono-centric cohort of patients affected by rheumatoid arthritis.

Objectives: The aim of this retrospective study was to evaluate baricitinib retention rate in patients affected by rheumatoid arthritis. Secondary aims were to compare the impact on treatment persistence of monotherapy and other variables such as systemic corticosteroid use, line of treatment, disease duration, sex, biomarkers positivity, and Herpes Zoster virus infection. Materials and methods: Patients with Rheumatoid Arthritis undergoing baricitinib were consecutively enrolled. Rheumatoid Arthritis diagnosis was performed with 2010 ACR/EULAR classification criteria. The cohort's demographic, clinical and therapeutical data were retrospectively collected. The whole follow-up duration was 104 weeks. Results: Ninety-five patients affected by rheumatoid arthritis and treated with baricitinib were consecutively enrolled. At the end of follow-up, the overall retention rate was 69.3%. No statistically significant difference in retention rate was observed between patients treated with baricitinib in monotherapy or in combination with methotrexate (p = 0.638) while patients undergoing a steroidal treatment showed a significantly reduced treatment retention (p = 0.028). Contrarily, patients treated with baricitinib as a first-line b/tsDMARD showed higher drug retention (p = 0.002) compared to further treatment lines. Steroid employment, steroid dosage and previous treatment with bDMARDs correlated with risk of treatment discontinuation and at univariate analysis (p = 0.028, p < 0.001, and p = 0.002 respectively). Multivariate analysis confirmed significance for higher steroid dosage and previous treatment with bDMARDs (p = 0.002 and p = 0.046). No adverse events such as deep venous thrombosis, pulmonary embolism or tubercular infection/reactivation were reported during the study observation. Conclusion: Our data show a good baricitinib retention rate after 12 and 24 months of observation (75.1 and 69.3%, respectively). In our cohort, concomitant treatment with methotrexate did not influence treatment persistence while retention was reduced in patients undergoing a steroidal treatment and/or in multi-failure subjects.

Intra-articular injections of biological disease-modifying anti-rheumatic drugs in inflammatory arthropathies: An up-to-date narrative review.

INTRODUCTION: Since the 1990s thebiological disease-modifying anti-rheumatic drugs (bDMARDs) have revolutionized the treatment of chronic dysimmune inflammatory arthropathies such as Rheumatoid Arthritis, Psoriatic Arthritis and Axial Spondylarthritis. Nevertheless, despite a full treatment regimen, mono- and oligoarticular persistence of the synovitis is sometimes observed. The intra-articular (IA) use of bDMARD drugs could resolve the persistent joint inflammation and result in a reduction in the degree of immunosuppression of individuals; moreover, the use of these drugs intra-articularly could be associated with a reduction in the treatment-related costs. METHODS: We extensively searched via PubMed and Google Scholar articles using as keywords "etanercept", "infliximab", "adalimumab", "certolizumab", "golimumab", "tocilizumab", "ixekizumab", "secukinumab", "rituximab" each combined with "intra-articular injection". RESULTS: We found and evaluated 161 papers, and then we selected 24 that were highly related to the topic of the present work. The articles examined a total of 349 patients, 85 males (M), and 168 females (F), mean age of 44.75±12.09 years old and considered 556 treated joints. Three hundred and forty-one patients were affected by Rheumatoid Arthritis, 198 by Psoriatic Arthritis, 56 by Axial Spondylarthritis, 26 by Juvenile Idiopathic Arthritis, 19 by Undifferentiated Arthritis, 1 by arthritis associated with inflammatory bowel disease and 9 patients by an unspecified inflammatory articular disorder. All patients were treated intra-articularly with a TNFα inhibitor among Adalimumab, Etanercept or Infliximab. Side effects were documented in 9 out of 349 (2.57%) treated patients and all were mild or moderate. In some cases the effectiveness of IA bDMARDs treatment was maintained for several months, however in the few published randomized controlled trials(RCTs) the corticosteroids (GCs) appeared to act better when administered intra-articularly compared to bDMARDs. CONCLUSIONS: The IA use of bDMARDs seems to be weakly effective in the management of resistant synovitis and not superior to GCs injections. The treatment's main limit appears to be the poor persistence of the compound in the joint.

Effects of antiresorptive agents on body composition: a case-control retrospective study.

Introduction: Osteoporosis is the most represented metabolic bone disease and is characterized by the reduction of bone mineral density (BMD), exposing patients to high fracture risk and disability. Bisphosphonates (BPs) are the main compounds exploited in treatment of osteoporosis and significantly reduce fracture risk. Sarcopenia is the pathological reduction of muscle masses and strength, and many studies highlighted its co-existence in patients with impaired bone mass. Indeed, the pathological reduction of lean tissue has been linked to a higher risk of falls and, consequently, fractures and disability. Moreover, the pathological reduction of lean tissue seems to share many pathological mechanisms with impaired bone strength and structure; thus, in this context, we decided to conduct a retrospective case-control study aimed at evaluating the effects of BPs on lean mass and body composition. Material and methods: We enrolled postmenopausal women from our metabolic bone diseases outpatient clinic who underwent at least two consecutive dual-energy X-ray absorptiometry (DXA) examinations concomitantly to the beginning of an antiresorptive agent. The body composition of patients and controls was compared by fat masses, lean masses and android-to-gynoid ratio (A/G ratio). Results: A total of 64 female subjects were considered for the study: 41 starting a BPs and 23 without treatment were used as control. The fat masses and lean masses appeared to be unaffected by BPs. Conversely, A/G ratio was lower in BPs group after 18 months of therapy compared to baseline (p < 0.05). From the stratification based on the single BP we failed to highlight any significant difference between the tested variables. Conclusions: Bisphosphonates treatment did not modify lean tissues, however a significant reduction of A/G ratio in BP group was documented. Thus the BPs seems to act on patients body composition and extra-skeletal tissues but larger prospective studies are needed to evaluate whether these modifications have clinical relevance.

Diagnostic role of minor salivary glands biopsy in Sjögren's syndrome: correlations between histology and autoimmunity in a large, monocentric cohort.

Introduction: Based on ACR/EULAR classification criteria, minor salivary glands biopsy (MSGB) is a useful diagnostic tool for the diagnosis of primary Sjögren's syndrome (SS). The main objective of our study was to evaluate the diagnostic role of MSGB, as well as to highlight correlations between histological findings and autoimmune profiles. Material and methods: We retrospectively evaluated histological and autoimmunity data from patients who underwent MSGB in our department in cases of suspected SS, from March 2011 to December 2018. Salivary gland samples were evaluated using Chisholm and Mason (CM) grading and the focus score (FS). Results: A total of 1,264 patients (108 males, 1,156 females) were included. The median age was 55.22 ±13.51 years (range: 15-87). In univariate binary logistic regression, CM ≥ 3 and FS ≥ 1 were significantly predicted by antinuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-Ro/SSA titer as well as anti-La/SSB, anti-Ro/SSA, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) positivity. In multivariate analysis, CM ≥ 3 and MSGB positivity were significantly associated with ANA titer; FS ≥ 1 was not associated with laboratory findings. A positive biopsy was associated with laboratory findings, as ANA and ENA titers, anti-Ro/SSA, anti-La/SSB, RF and ACPA positivity may discriminate patients with SS-related histological findings. Conclusions: Minor salivary glands biopsy is a useful tool to diagnose SS in cases of highly suggestive clinical symptoms but in the absence of a specific autoimmunity.

Peripheral Macrovascular Involvement in Systemic Sclerosis: A Cohort Study by Color and Spectral Doppler Ultrasonography.

OBJECTIVES: Systemic sclerosis (SSc) is a disease characterized by diffuse sclerosis of skin and organs and small vessel vasculopathy. Despite it, large vessels can also be involved with ulnar artery vasculopathy, revealing as a more frequent feature of SSc. The aim of this paper is to assess the macrovascular involvement of SSc patients through an ultrasound (US) evaluation of radial and ulnar arteries. METHODS: Radial and ulnar resistance indices (RIs) and peak systolic velocity (PV) (cm/s) together with clinical features of SSc patients were evaluated. Raynaud phenomenon (RP) and healthy control (HC) groups were used for comparison. RESULTS: Forty-three SSc patients were evaluated. Twelve patients (28%) had ulnar artery occlusions (UAOs). In nine cases (75%), UAOs were bilateral. A high UAO prevalence (42%) was found in SSc patients with late nailfold-video-capillaroscopy (NVC) pattern (p = 0.0264). Patients with UAOs had digital ulcers (DUs) in 10 cases (83.3%). Radial and ulnar PVs were lower in SSc and RP patients than the HC group. Radial and ulnar RIs were higher in SSc and RP patients than the HC group. A decision tree analysis led to the classification of 70% of SSc patients with an ulnar RI > 0.82 and ulnar PV > 2.8 cm/s. The most influential variables on UAO development were interstitial lung disease (ILD) (p = 0.002) and NVC pattern (p = 0.002). A positive correlation was shown between modified Rodnan skin score (mRSS) and ILD (p = 0.283; r = 0.033), mRSS and DU (r = 0.344; p = 0.012) and DU and ILD (r = 0.303; p = 0.024). Male sex was associated with increased UAO frequency (p = 0.042). CONCLUSIONS: UAO is a peculiar feature of severe SSc present in 28% of the cases, particularly associated with the presence of ILD and late NVC pattern. In 75% of the cases, UAOs are bilateral. DUs are very frequent in patients with UAOs (83%). The RI evaluated by US could be useful to distinguish SSc from HC patients. US could be a useful tool for assessing high-risk DU development in patients.

Ultrasound guided corticosteroids sacroiliac joint injections (SIJIs) in the management of active sacroiliitis: a real-life prospective experience.

INTRODUCTION: Active sacroiliitis represents the hallmark of axial spondyloarthritis (axSpA) and manifests as inflammatory low back pain associated with morning stiffness (MS). Sometimes, the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and biological disease modifying drugs (bDMARDs) proves unsatisfactory in achieving a remission. MATERIALS AND METHODS: We enrolled patients affected with active sacroiliitis confirmed via magnetic resonance imaging (MRI) and treated with a corticosteroid sacroiliac joint injection (SIJI) via ultrasound guidance. After SIJI, we evaluated visual-analogue scale (VAS) and MS pain changes. As controls, we selected axSpA patients starting bDMARDs. RESULTS: We enrolled 26 patients (mean age 55 ± 14 years; 25 females and 1 male; > 95% treated with NSAIDs; 46% on bDMARDs; 75.82 ± 123 months) and examined a total of 47 treated joints. We detected a 48% reduction in VAS pain after 24 h. Moreover, we observed a significant reduction (p < 0.0001) of VAS pain between the baseline and every subsequent follow-up visit. Further, a significant difference in VAS pain compared to the baseline in the controls was observed starting from week 12. There was a significant reduction in MS after 1 week due to SIJIs, while in the controls the first significant change from the baseline in MS was detected after 12 weeks. The efficacy of infiltrative therapy lasted up to 6 months: persistent VAS as well as MS pain reduction was observed. CONCLUSIONS: US-guided SIJI represents an effective and safe technique for patients who have active sacroiliitis yet are ineligible for biologic treatment or who experience unsatisfactory disease control despite receiving therapy.

Accuracy of power Doppler ultrasonography in the diagnosis and monitoring of idiopathic inflammatory myopathies.

OBJECTIVES: No clear-cut guidelines exist for the use of imaging procedures for the diagnosis of idiopathic inflammatory myopathies (IIM). The aim of the present study was to assess the diagnostic accuracy of power Doppler ultrasonography (PDUS) score in IIM patients compared with a control group and its usefulness during follow-up. METHODS: All patients evaluated in the Vasculitis and Myositis Clinic, Rheumatology Unit, University of Siena were prospectively collected. All patients underwent US examination of both thighs in axial and longitudinal scans, which were also performed twice (T1) or three times (T2). RESULTS: Forty-five patients with IIM (median [interquartile range] age 55 [45-66] years; 35 female) were enrolled. Receiver operating characteristic curves distinguished patients and controls based on ∑power Doppler (PD), ∑oedema, ∑atrophy and CRP. The best cut-off value for ∑PD was 0.5, ∑oedema 1.5, ∑atrophy 0.5 and CRP 0.22 mg/dl. In a logistic regression analysis, the variables that most influenced diagnosis of IIM were ∑PD and ∑oedema (P = 0.017 and P = 0.013, respectively). ∑Oedema was lower at T1 (P = 0.0108) and T2 (P = 0.0012) than at T0. Likewise, ∑PD was lower at T1 (P = 0.0294) and T2 (P = 0.0420) than at T0. Physician global assessment was lower at T1 (P = 0.0349) and T2 (P = 0.0035) than at baseline. CONCLUSION: Our findings show that PDUS is a reliable diagnostic tool in the differential diagnosis between inflammatory and non-inflammatory myopathies. Moreover, PDUS can be employed also during the follow-up of patients with IIM. A reduction in disease activity, measured by physician global assessment, led to a concomitant decrease in both oedema and PD, which was directly correlated with their rate of change. This underlines the close link between clinical assessment and PDUS findings, not only at diagnosis but also during monitoring.

Bone-sparing effects of tocilizumab in rheumatoid arthritis: a monocentric observational study.

Introduction: Bone loss is a common feature in several autoimmune and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Indeed, the high levels of pro-inflammatory cytokines seem to enhance bone resorption and to diminish bone formation, thus producing an uncoupling between osteoclast and osteoblast function and favoring the onset of juxtarticular as well as systemic osteoporosis. Many papers underline the high prevalence of osteoporosis in RA, as well as the negative correlation between interleukin 6 (IL-6) serum levels and bone mineral density (BMD). The aim of this study was to assess the effectiveness of one-year treatment with tocilizumab (TCZ), the first approved IL-6 receptor inhibitor, in reducing bone loss in RA. Material and methods: We enrolled 18 patients fulfilling 2010 ACR and EULAR criteria for RA from our arthritis outpatient clinic, assessing clinical and biochemical parameters during a 12-month period. The patients received TCZ 8 mg/kg i.v. every 4 weeks and underwent dual energy X-ray absorptiometry (DXA) for the measurement of bone mineral density (BMD) at baseline and at the end of study. Serum levels of C-reactive protein (CRP), erythrocytes sedimentation rate (ESR), IL-6, serum CrossLaps, osteoprotegerin (OPG), receptor activator of nuclear factor κß ligand (RANK-L) and dickkopf-1 (DKK-1) were measured at baseline, at 6 months and 1 year. Results: No significant difference in IL-6, RANK-L, DKK-1, OPG and serum CrossLaps levels between baseline, 6 months and 1 year were found. A significant increase of lumbar spine BMD was evidenced after 1 year of TCZ treatment. No difference in total body and femoral neck BMD was documented the end of the study. Conclusions: This study suggest the bone-sparing effect of TCZ in RA affected individuals.

A Novel Ultrasonographic Anthropometric-Independent Measurement of Median Nerve Swelling in Carpal Tunnel Syndrome: The "Nerve/Tendon Ratio" (NTR).

Background: There is little consensus on ultrasound (US) normative values of cross-sectional area of median nerve (MN-CSA) in carpal tunnel syndrome (CTS) because of its dependency on anthropometric parameters. We aim to propose a novel anthropometric-independent US parameter: MN-CSA/flexor radialis carpi CSA (FCR-CSA) ratio ("Nerve Tendon Ratio", NTR), in the diagnosis of clinically and electrodiagnostic (EDS)-defined CTS. Methods: 74 wrists of 49 patients with clinically defined CTS underwent EDS (scored by the 1−5 Padua Scale of electrophysiological severity, PS) and US of carpal tunnel with measurement of MN-CSA (at the carpal tunnel inlet), FCR-CSA (over scaphoid tubercle) and its ratio (NTR, expressed as a percentage). US normality values and intra-operator agreement were assessed in 33 healthy volunteers. Results: In controls, the mean MN-CSA was 5.81 mm2, NTR 64.2%. In 74 clinical CTS, the mean MN-CSA was 12.1 mm2, NTR 117%. In severe CTS (PS > 3), the mean MN-CSA was 15.9 mm2, NTR 148%. In CTS, both MN-CSA and NTR correlated with sensitive conduction velocity (SCV) (p < 0.001), distal motor latency (DML) (p < 0.001) and PS (p < 0.001), with a slight superiority of NTR vs. MN-CSA when controlled for height, wrist circumference and weight. In CTS filtered for anthropometric extremes, only NTR maintained a correlation with SCV (p = 0.023), DML (p = 0.016) and PS (p = 0.009). Diagnostic cut-offs were obtained with a binomial regression analysis. In those patients with a clinical diagnosis of CTS, the cut-off of MN-CSA (AUROC: 0.983) was 8 mm2 (9 mm2 with highest positive predictive value, PPV), while for NTR (AUROC: 0.987), the cut-off was 83% (100% with highest PPV). In patients with EDS findings of severe CTS (PS > 3), the MN-CSA (AUROC: 0.876) cut-off was 12.3 mm2 (15.3 mm2 with highest PPV), while for NTR (AUROC: 0.858) it was 116.2% (146.0% with highest PPV). Conclusions: NTR can be simply and quickly calculated, and it can be used in anthropometric extremes.

A conformational switch controlling the toxicity of the prion protein.

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond ('H-latch'), altering the flexibility of the α2-α3 and ß2-α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.

Routine IgG4 staining in minor salivary gland biopsy in a cohort of Italian Caucasian patients suffering from xerostomia.

Objectives: IgG4-related disease is a potentially systemic disease mimicking and overlapping with different autoimmune diseases, such as primary Sjögren's syndrome (pSS). The involvement of salivary glands, previously called Mikulicz's disease, has been reclassified as IgG4-related sialadenitis (SA). The aim of this study was to assess the prevalence of IgG4-SA in a cohort of Italian Caucasian patients presenting with xerostomia and to evaluate the eventual overlap between IgG4-SA and pSS. Material and methods: We included 154 patients - 15 males and 139 females, mean age 54.18 ±14.24 years, who underwent minor salivary gland biopsy between March and December 2019 for xerostomia. Histopathology was evaluated using Chisholm-Mason (CM) and focus score (FS) for pSS and immunohistochemical study with IgG4 staining for IgG4-SA were performed. Serum autoantibodies (anti-SSa/RoAb, anti-SSB/LaAb, antinuclear antibodies, rheumatoid factor) were also assessed. Results: In 69 patients (44.8%) FS 0 was found, while FS ≥ 1 was presented in 85 (55.2%). Chisholm-Mason score < 3 and CM ≥ 3 was found in 73 (47.4%) and 81 (52.6%) cases, respectively. IgG4/high-power field level was 20 in 3 pSS patients (1.9%), but none of them had an IgG4/IgG ratio ≥ 40, as well as tissue fibrosis with storiform pattern, obliterative vasculitis, and tissue eosinophilia. The diagnosis of pSS, was confirmed in 92 patients (59.74%). No patient was definitively diagnosed with an IgG4-related disease. Conclusions: In the case of xerostomia, the evaluation of the histopathological specimen for IgG4 should not be routinely performed, at least in an Italian-based Caucasian population. Moreover, immunohistochemistry should not be requested in the case of a negative result of biopsy for pSS.

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

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.

Diffuse Peripheral Enthesitis in Metabolic Syndrome: A Retrospective Clinical and Power Doppler Ultrasound Study / Entesitis periférica difusa en el síndrome metabólico: estudio clínico retrospectivo y de ecografía Power Doppler

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.(AU)

Objetivos: Estudiar la entesitis periférica con ecografía Power Doppler (PDUS) en pacientes que presentan dolor lumbar (DL) y síndrome metabólico (SM), en comparación con los pacientes con DL únicamente, para correlacionar las puntuaciones ecográficas con las características clínico-antroprométicas, y definir cualquier relación entre entesitis y síndrome de hiperostosis idiopática difusa (DISH). Métodos: Se evaluaron 60 pacientes con DL y SM mediante PDUS para entesitis de múltiples sitios, valorando retrospectivamente los cambios inflamatorios y de daños estructurales. Un grupo de 60 sujetos con DL y sin SM fue evaluado utilizando el mismo protocolo, como grupo control. Resultados: Los pacientes reflejaron sobrepeso (IMC 29,8) y estado inflamatorio de bajo grado (proteína C reactiva [PCR] 0,58 mg/dL, tasa de eritrosedimentación [TES] 20,2 mm/h). Se demostró entesitis en 52 (86%) pacientes (17,6% entesis), y ocho controles (13,3%) (p < 0,00001). Las señales PD (15% de pacientes) estuvieron asociadas a dolor debido a entesitis (p = 0,0138). Las puntuaciones ecográficas se correlacionaron con índice de masa corporal (IMC), dolor y diabetes tipo 2. En 28 (46%) pacientes se diagnosticó DISH concurrente, correlacionado con edad avanzada (p < 0,0001), PCR (p = 0,0428), TES (p = 0,0069) y puntuaciones PDUS (p = 0,0312 inflamatoria, p = 0,0071 estructural). El SM tuvo una fuerte asociación (OR 4,375, p = 0,0007) con DISH concurrente. Conclusiones: La entesitis periférica difusa es muy común en el SM. Casi la mitad de los pacientes con SM pueden tener diagnóstico concurrente de DISH; son pacientes de edad avanzada, con mayor inflamación, y mayores puntuaciones de entesitis mediante PDUS.(AU)