Comparison of Digital versus Analog 68Ga-PSMA-11 PET/CT Performance in Hormone-Sensitive Prostate Cancer Patients with Early Biochemical Recurrence or Persistence after Radical Treatment.

The aim of this study was to investigate whether the favorable characteristics of novel digital PET/CT (dPET) scanners compared to analog systems (aPET) could translate into an improved disease localization in prostate cancer (PCa) patients with early biochemical recurrence/persistence (BCR/BCP). A retrospective analysis was conducted on 440 consecutive analog (n = 311) or digital (n = 129) 68Ga-PSMA-11 PET/CT scans performed in hormone-sensitive ADT-free PCa patients with early-BCR/BCP (PSA at PET ≤ 2.0 ng/mL), previously treated with radical intent (radical-prostatectomy/radiotherapy). dPET showed a higher positivity rate compared to aPET (48.8% [63/129] vs. 37.3% [116/311], p = 0.03), despite the slightly lower median PSA value of the dPET cohort (0.33 [IQR: 0.26-0.61] vs. 0.55 [IQR: 0.40-0.85] ng/mL, p < 0.01). dPET detection rate was higher in both PSA ranges 0.2-0.5 ng/mL (39.0% [32/82] vs. 25.2% [34/135], p = 0.03) and 0.5-1.0 ng/mL (63.2% [24/38] vs. 40.8% [53/130], p = 0.02), but not for PSA ≥ 1.0 ng/mL. dPET detected a higher per patient median number of pathologic findings (PSMA-RADS ≥ 3) and multi-metastatic cases (>3 lesions) among N1/M1-positive scans (21.7% [10/46] vs. 8.6% [9/105], p = 0.03). Moreover, the proportion of uncertain findings among pathological lesions was significantly lower for dPET than aPET (24.4% [39/160] vs. 38.5% [60/156], p = 0.008). Overall, 68Ga-PSMA-11 dPET showed a better performance compared to aPET, resulting in a higher scan-positivity rate, a higher number of detected pathological lesions, and a lower rate of uncertain findings.

Osteoimmunology of Spondyloarthritis.

The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA.

Machine Learning CT-Based Automatic Nodal Segmentation and PET Semi-Quantification of Intraoperative 68Ga-PSMA-11 PET/CT Images in High-Risk Prostate Cancer: A Pilot Study.

High-resolution intraoperative PET/CT specimen imaging, coupled with prostate-specific membrane antigen (PSMA) molecular targeting, holds great potential for the rapid ex vivo identification of disease localizations in high-risk prostate cancer patients undergoing surgery. However, the accurate analysis of radiotracer uptake would require time-consuming manual volumetric segmentation of 3D images. The aim of this study was to test the feasibility of using machine learning to perform automatic nodal segmentation of intraoperative 68Ga-PSMA-11 PET/CT specimen images. Six (n = 6) lymph-nodal specimens were imaged in the operating room after an e.v. injection of 2.1 MBq/kg of 68Ga-PSMA-11. A machine learning-based approach for automatic lymph-nodal segmentation was developed using only open-source Python libraries (Scikit-learn, SciPy, Scikit-image). The implementation of a k-means clustering algorithm (n = 3 clusters) allowed to identify lymph-nodal structures by leveraging differences in tissue density. Refinement of the segmentation masks was performed using morphological operations and 2D/3D-features filtering. Compared to manual segmentation (ITK-SNAP v4.0.1), the automatic segmentation model showed promising results in terms of weighted average precision (97-99%), recall (68-81%), Dice coefficient (80-88%) and Jaccard index (67-79%). Finally, the ML-based segmentation masks allowed to automatically compute semi-quantitative PET metrics (i.e., SUVmax), thus holding promise for facilitating the semi-quantitative analysis of PET/CT images in the operating room.

Robot-assisted PSMA-radioguided Surgery to Assess Surgical Margins and Nodal Metastases in Prostate Cancer Patients: Report on Three Cases Using an Intraoperative PET-CT Specimen Imager.

INTRODUCTION: The aim of this feasibility study was to test the intraoperative use of this brand-new specimen PET/CT to guide robot-assisted radical prostatectomy and pelvic lymph node dissection. MATERIALS AND METHODS: Three cases of robot-assisted radical prostatectomy and pelvic lymph node dissection were performed with intraoperative use of the specimen imager. Surgeries were performed with Da Vinci Xi robot. An intravenous injection of 68Ga-PSMA-11 was performed in the OR and after complete excision, the specimens were analyzed with the imager. RESULTS: The average nodal yield was 17.3 (5.8 SD) nodes per patient. Specimen PET/CT images showed a focal uptake in a metastatic node (TBR 13.6), and no uptake or diffuse, faint uptake in negative nodes (TBR range: 1-5.3). The specimen imager provided intraoperative PET/CT images that clearly showed negative surgical margins in two patients, whereas the results were uncertain in a locally advanced case. CONCLUSION: The intraoperative use of the specimen PET/CT imager is safe and feasible and could improve the evaluation of prostate surgical margins and lymph node status.

Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study.

Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan-Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8-91.5%) at month 12, 78.8% (95% CI: 78.8-85.2%) at month 24, 63.8% (95% CI: 55.1-73.8%) at month 36, and 59.9% (95% CI: 55.1-73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results.

99mTc-Tilmanocept performance for sentinel node mapping in breast cancer, melanoma, and head and neck cancer: a systematic review and meta-analysis from a European expert panel.

PURPOSE: Although multiple radiopharmaceuticals are currently available for sentinel node (SN) biopsy, 99mTc-tilmanocept is of particular interest due to its low molecular weight and specific binding capability for the mannose receptors of lymphatic reticuloendothelial cells. In the current systematic review and meta-analysis, we aimed to provide an update from a European expert panel on the performance of 99mTc-tilmanocept for SN biopsy. METHODS: A systematic literature search of the PubMed/Medline and Embase databases was performed to identify studies on the use of 99mTc-tilmanocept for SN identification in oncological patients. The articles' methodological quality was assessed before inclusion. The pooled estimates of the pre-/intraoperative detection rates (DR; proportion of patients with ≥ 1 SN identified) and/or pN + sensitivity (SN + /pN + patients ratio), with 95% confidence intervals (CIs), were calculated for breast cancer, melanoma, and head and neck cancer. RESULTS: Twenty-four articles were included in the systematic review, and twenty-one provided data for the meta-analysis. According to data availability, the 99mTc-tilmanocept-estimated pooled preoperative and intraoperative DRs were 0.94 (95%CI, 0.88-1.01) and 0.99 (0.98-1.00) for breast cancer, 0.98 (0.96-0.99) and 1.00 (0.99-1.00) for melanoma, and 0.97 (0.93-1.02) and 0.99 (0.96-1.01) for head and neck carcinoma. Finally, the pooled sensitivity for nodal metastasis in melanoma was 0.97 (95% CI, 0.92-1.03). CONCLUSION: 99mTc-tilmanocept is a promising radiotracer for SN mapping in patients with breast cancer, melanoma, or head and neck cancer. We strongly believe that multicenter trials are still needed to assess if 99mTc-tilmanocept is superior to other radiotracers used in clinical routine.

Artificial Intelligence in Breast Cancer: A Systematic Review on PET Imaging Clinical Applications.

BACKGROUND: 18F-FDG PET/CT imaging represents the most important functional imaging method in oncology. European Society of Medical Oncology and the National Comprehensive Cancer Network guidelines defined a crucial role of 18F-FDG PET/CT imaging for local/locally advanced breast cancer. The application of artificial intelligence on PET images might potentially contributes in the field of precision medicine. OBJECTIVE: This review aims to summarize the clinical indications and limitations of PET imaging for comprehensive artificial intelligence in relation to breast cancer subtype, hormone receptor status, proliferation rate, and lymphonodal (LN)/distant metastatic spread, based on recent literature. METHODS: A literature search of the Pubmed/Scopus/Google Scholar/Cochrane/EMBASE databases was carried out, searching for articles on the use of artificial intelligence and PET in breast tumors. The search was updated from January 2010 to October 2021 and was limited to original articles published in English and about humans. A combination of the search terms "artificial intelligence", "breast cancer", "breast tumor", "PET", "Positron emission tomography", "PET/CT", "PET/MRI", "radiomic"," texture analysis", "machine learning", "deep learning" was used. RESULTS: Twenty-three articles were selected following the PRISMA criteria from 139 records obtained from the Pubmed/Scopus/Google Scholar/Cochrane/EMBASE databases according to our research strategy. The QUADAS of 30 full-text articles assessed reported seven articles that were excluded for not being relevant to population and outcomes and/or for lower level of evidence. The majority of papers were at low risk of bias and applicability. The articles were divided per topic, such as the value of PET in the staging and re-staging of breast cancer patients, including new radiopharmaceuticals and simultaneous PET/MRI. CONCLUSION: Despite the current role of AI in this field remains still undefined, several applications for PET/CT imaging are under development, with some preliminary interesting results particularly focused on the staging phase that might be clinically translated after further validation studies.

Development of a REDCap-based workflow for high-volume relational data analysis on real-time data in a medical department using open source software.

BACKGROUND/AIM: The current availability of large volumes of clinical data has provided medical departments with the opportunity for large-scale analyses, but it has also brought forth the need for an effective strategy of data-storage and data-analysis that is both technically feasible and economically sustainable in the context of limited resources and manpower. Therefore, the aim of this study was to develop a widely-usable data-collection and data-analysis workflow that could be applied in medical departments to perform high-volume relational data analysis on real-time data. METHODS: A sample project, based on a research database on prostate-specific-membrane-antigen/positron-emission-tomography scans performed in prostate cancer patients at our department, was used to develop a new workflow for data-collection and data-analysis. A checklist of requirements for a successful data-collection/analysis strategy, based on shared clinical research experience, was used as reference standard. Software libraries were selected based on widespread availability, reliability, cost, and technical expertise of the research team (REDCap-v11.0.0 for collaborative data-collection, Python-v3.8.5 for data retrieval and SQLite-v3.31.1 for data storage). The primary objective of this study was to develop and implement a workflow to: a) easily store large volumes of structured data into a relational database, b) perform scripted analyses on relational data retrieved in real-time from the database. The secondary objective was to enhance the strategy cost-effectiveness by using open-source/cost-free software libraries. RESULTS: A fully working data strategy was developed and successfully applied to a sample research project. The REDCap platform provided a remote and secure method to collaboratively collect large volumes of standardized relational data, with low technical difficulty and role-based access-control. A Python software was coded to retrieve live data through the REDCap-API and persist them to an SQLite database, preserving data-relationships. The SQL-language enabled complex datasets retrieval, while Python allowed for scripted data computation and analysis. Only cost-free software libraries were used and the sample code was made available through a GitHub repository. CONCLUSIONS: A REDCap-based data-collection and data-analysis workflow, suitable for high-volume relational data-analysis on live data, was developed and successfully implemented using open-source software.

Predictors of Bone Metastases at 68Ga-PSMA-11 PET/CT in Hormone-Sensitive Prostate Cancer (HSPC) Patients with Early Biochemical Recurrence or Persistence.

Prostate-specific-membrane-antigen/positron-emission-tomography (PSMA-PET) can accurately detect disease localizations in prostate cancer (PCa) patients with early biochemical recurrence/persistence (BCR/BCP), allowing for more personalized image-guided treatments in oligometastatic patients with major impact in the case of bone metastases (BM). Therefore, this study aimed to identify predictors of BM at PSMA-PET in early-BCR/BCP hormone-sensitive PCa (HSPC) patients, previously treated with radical intent (radiotherapy or radical prostatectomy ± salvage-radiotherapy (SRT)). A retrospective analysis was performed on 443 68Ga-PSMA-11-PET/CT scans. The cohort median PSA at PET-scan was 0.60 (IQR: 0.38-1.04) ng/mL. PSMA-PET detection rate was 42.0% (186/443), and distant lesions (M1a/b/c) were found in 17.6% (78/443) of cases. BM (M1b) were present in 9.9% (44/443) of cases, with 70.5% (31/44) showing oligometastatic spread (≤3 PSMA-positive lesions). In the multivariate binary logistic regression model (accuracy: 71.2%, Nagelkerke-R2: 13%), T stage ≥ 3a (OR: 2.52; 95% CI: 1.13-5.60; p = 0.024), clinical setting (previous SRT vs. first-time BCR OR: 2.90; 95% CI: 1.32-6.35; p = 0.008), and PSAdt (OR: 0.93; 95% CI: 0.88-0.99; p = 0.026) were proven to be significant predictors of bone metastases, with a 7% risk increment for each single-unit decrement of PSAdt. These predictors could be used to further refine the indication for PSMA-PET in early BCR/BCP HSPC patients, leading to higher detection rates of bone disease and more personalized treatments.

The role of PET/CT in thyroid autoimmune diseases.

Autoimmune thyroid diseases (AITD) are a heterogeneous group of disorders. They include, in particular, Graves' disease and Hashimoto's thyroiditis with a wide range of different functional status ranging from subclinical biochemical abnormalities to severe hyperthyroidism or severe hypothyroidism respectively. Furthermore, other conditions more frequently infectious or drug related can cause an immune reaction in the thyroid tissue. In AITDs, positron emission tomography/computed tomography (PET/CT) does not play a primary role for disease diagnosis or management, but accidental findings can occur in both symptomatic and asymptomatic patients, and they should be recognized and well interpreted. A comprehensive literature search of the PubMed databases was conducted to identify papers (systematic review, prospective and retrospective study, case report) evaluating the role of PET/CT in thyroid autoimmune diseases. Thyroid diffuse uptake of 18F-fluoro-2-deoxy-2-d-glucose ([18F]FDG) has been shown to be frequently associated with AITDs, but also with immune-induced thyroid disorders related to SARS-CoV-2 or immunotherapy, while malignant lesions more often have a focal aspect. Other radiopharmaceuticals as [68Ga]-DOTA-peptides, [68Ga]-fibroblast activation protein inhibitors (FAPIs) and [68Ga]-prostate specific membrane antigen ([68Ga]-PSMA) showed similar findings. In conclusion, PET/CT scan in AITDs does not play a primary role in the diagnosis, but the occasional finding of a thyroid uptake must always be described in the report and possibly investigated for a better patient's management.

Event-free survival after 68 Ga-PSMA-11 PET/CT in recurrent hormone-sensitive prostate cancer (HSPC) patients eligible for salvage therapy.

BACKGROUND/AIM: Prostate-specific-membrane-antigen/positron emission tomography (PSMA-PET) detects with high accuracy disease-recurrence, leading to changes in the management of biochemically-recurrent (BCR) prostate cancer (PCa). However, data regarding the oncological outcomes of patients who performed PSMA-PET are needed. The aim of this study was to evaluate the incidence of clinically relevant events during follow-up in patients who performed PSMA-PET for BCR after radical treatment. MATERIALS AND METHODS: This analysis included consecutive, hormone-sensitive, hormone-free, recurrent PCa patients (HSPC) enrolled through a prospective study. All patients were eligible for salvage therapy, having at least 24 months of follow-up after PSMA-PET. The primary endpoint was the Event-Free Survival (EFS), defined as the time between the PSMA-PET and the date of event/last follow-up. The Kaplan-Meier method was used to estimate the EFS curves. EFS was also investigated by Cox proportional hazards regression. Events were defined as death, radiological progression, or PSA recurrence after therapy. RESULTS: One-hundred and seventy-six (n = 176) patients were analyzed (median PSA 0.62 [IQR: 0.43-1.00] ng/mL; median follow-up of 35.4 [IQR: 26.5-40.3] months). The EFS was 78.8% at 1 year, 65.2% (2 years), and 52.2% (3 years). Patients experiencing events during study follow-up had a significantly higher median PSA (0.81 [IQR: 0.53-1.28] vs 0.51 [IQR: 0.36-0.80] ng/mL) and a lower PSA doubling time (PSAdt) (5.4 [IQR: 3.7-11.6] vs 12.7 [IQR: 6.6-24.3] months) (p < 0.001) compared to event-free patients. The Kaplan-Meier curves showed that PSA > 0.5 ng/mL, PSAdt ≤ 6 months, and a positive PSMA-PET result were associated with a higher event rate (p < 0.01). No significant differences of event rates were observed in patients who received changes in therapy management after PSMA-PET vs. patients who did not receive therapy changes. Finally, PSA > 0.5 ng/mL and PSAdt ≤ 6 months were statistically significant event-predictors in multivariate model (p < 0.001). CONCLUSION: Low PSA and long PSAdt were significant predictors of longer EFS. A lower incidence of events was observed in patients having negative PSMA-PET, since longer EFS was significantly more probable in case of a negative scan.

Correlation between parotid saliva composition and dental caries using 31P-NMR and ICDAS score.

OBJECTIVES: The preservation of enamel mineral is influenced by the supersaturation of salivary secretions with respect to calcium phosphate salts. The aim was to measure the chemical environmental state of phosphate ions in a subject's parotid saliva, and to correlate this with their dental caries score, by means of 31P-Nuclear Magnetic Resonance Spectroscopy (31P-NMR) and the International Caries Detection and Assessment System (ICDAS). DESIGN: Unilateral paraffin wax stimulated parotid saliva samples were collected from 21 healthy adult subjects using a Lashley cup. The flowrate was recorded during collection. Clinical caries scores of each subject were classified using the ICDAS score. The pH was recorded for each saliva sample. 31P-NMR spectra of each saliva sample were obtained to determine the phosphorus chemical environment. All the collected data were analysed by Pearson's correlation. RESULTS: Parotid saliva flow rates were in the range from 0.07 to 0.56 ml/min. The pH varied from 5.9 to 7.6. Each 31P-NMR spectrum showed a single broad line with a chemical shift between 0.07 and 2.38 ppm. At neutral pH the maximum chemical shift was 2.05 ppm, whereas at a lower pH values the phosphorous chemical shift reduced, to 0.34 at pH 5.9. The flowrate and the 31P-NMR chemical shift correlated positively (r = 0.71; p < 0.05). The ICDAS score correlated negatively with the 31P-NMR chemical shift (r = 0.43; p < 0.05). CONCLUSIONS: This parotid saliva 31P-NMR study has shown that different phosphate states exist within saliva, which significantly influence its inorganic chemical behaviour, and therefore its cariostatic activity.

Radiation dose in nuclear medicine: the hybrid imaging.

Hybrid imaging procedures such as single-photon emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/computed tomography (PET/CT) showed a rapid diffusion in recent years because of their high sensitivity, specificity, and accuracy, due to a more accurate localization and definition of scintigraphic findings. However, hybrid systems inevitably lead to an increase in patient radiation exposure because of the added CT component. Effective doses due to the radiopharmaceuticals can be estimated by multiplying the administered activities by the effective dose coefficients, while for the CT component the dose-length product can be multiplied by a conversion coefficient k. However, the effective dose value is subject to a high degree of uncertainty and must be interpreted as a broad, generic estimate of biologic risk. Although the effective dose can be used to estimate and compare the risk of radiation exposure across multiple imaging techniques, clinicians should be aware that it represents a generic evaluation of the risk derived from a given procedure to a generic model of the human body. It cannot be applied to a single individual and should not be used for epidemiologic studies or the estimation of population risks due to the inherent uncertainties and oversimplifications involved. Practical ways to reduce radiation dose to patients eligible for hybrid imaging involve adjustments to both the planning phase and throughout the execution of the study. These methods include individual justification of radiation exposure, radiopharmaceutical choice, adherence to diagnostic reference levels (DLR), patient hydration and bladder voiding, adoption of new technical devices (sensitive detectors or collimators) with new reconstruction algorithms, and implementation of appropriate CT protocols and exposure parameters.

Effectiveness of Adalimumab for the Treatment of Psoriatic Arthritis: An Italian Real-Life Retrospective Study.

Background: Few studies have evaluated the effectiveness of adalimumab in the real-life setting in psoriatic arthritis (PsA). Objective: To evaluate the 2-year retention rate of adalimumab in PsA patients. Potential baseline parameters influencing persistence on treatment were also evaluated. Methods: PsA patients from 16 Italian Rheumatology Units treated with adalimumab as first- or second-line biological therapy were retrospectively evaluated. Adalimumab retention rate was evaluated at 12 and 24 months. Logistic regression was used to evaluate the association between predictor variables and adalimumab retention rate. Results: From 424 patients (53.5% male, aged 48.3 ± 12.8 years) who started treatment with adalimumab, 367 (86.6%) maintained treatment for 12 months and 313 (73.8%) for 2 years. At 24-months, Disease Activity in PsA (DAPSA) remission (defined as ≤4) and Low Disease Activity (LDA) (≤14) were achieved in 22.8% and 44.4% of patients, respectively. Adalimumab treatment significantly decreased the number of tender (7.0 ± 5.7 at baseline vs. 2.3 ± 3.5 at 24 months, p < 0.001) and swollen joints (2.7 ± 2.8 at baseline vs. 0.4 ± 0.9 at 24 months, p < 0.001), DAPSA (25.5 ± 10.9 at baseline vs. 11.0 ± 8.4 at 24 months, p < 0.001), PASI (5.3 ± 5.7 at baseline vs. 2.7 ± 2.8 at 24 months, p < 0.001) and CRP (3.8 ± 6.3 at baseline vs. 1.2 ± 1.7 at 24 months, p < 0.001). Among a range of laboratory and clinical variables, only female gender was associated with improved adalimumab persistence at 24 months (OR: 1.98, 95% CI: 1.2-3.2, p = 0.005). Conclusions: Independent of a range of predictor variables, adalimumab was shown to be effective, while maintaining a high retention rate after 2 years in PsA patients.

Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebo-controlled study.

The aim of this study was to evaluate differences in T helper cell sub-types and osteoclast (OCs) precursors in peripheral blood between patients affected by early rheumatoid arthritis (eRA) and healthy controls. The effect of administration of cholecalcipherol on clinical and laboratory parameters was subsequently evaluated, by a parallel, randomized double blind, placebo controlled trial. Thirty nine eRA patients and 31 age-matched controls were enrolled and compared for levels of 25OH vitamin D, T helper cell sub-types, OCs precursors including both classical and non-classical and pro-inflammatory cytokines at baseline. Eligible patients were female ≥18 years of age with a diagnosis of RA, as defined by the American College of Rheumatology 2010 criteria for <6 months prior to inclusion in the study. Patients with auto-immune or inflammatory diseases other than RA were excluded. Patients treated with glucocorticoids (GCs), disease modifying activity drugs and biologic agents within the past 6 months were also excluded. In the second phase of the study, eRA patients were randomly assigned to standard treatment with methotrexate (MTX) and GCs with (21) or without (18) cholecalcipherol (300,000 IU) and followed for 3 months; the randomization was done by computer generated tables to allocate treatments. Three patients didn't come back to the follow up visit for personal reasons. None of the patients experienced adverse events. The main outcome measures were T cells phenotypes, OCs precursors and inflammatory cytokines. Secondary outcome measure were clinical parameters. In eRA, 25OH vitamin D levels were significantly lower. CD4+/IFNγ+,CD4+/IL4+, CD4+/IL17A+ and CD4+IL17A+IFNγ+, cells were increased in eRA as well as non-classical OCs precursors, whereas T regulatory cells were not altered. TNFα, TGFß1, RANKL, IL-23 and IL-6 were increased in eRA. Non-classical OCs, IL-23 and IL-6 correlated with disease severity and activity. Standard treatment with MTX and GC ameliorated clinical symptoms and reduced IL-23, whereas it did not affect CD4+ cells sub-sets nor OCs precursors. After 3 months, the combined use of cholecalcipherol significantly ameliorated the effect of treatment on global health. In eRA, a significant imbalance in T CD4+ sub-types accompanied by increased levels of non-classical OCs precursors and pro-inflammatory cytokines was observed. A single dose of cholecalcipherol (300,000 IU) combined with standard treatment significantly ameliorates patients general health.

Low Risk of Hepatitis B Virus Reactivation in HBsAg-negative/Anti-HBc-positive Carriers Receiving Rituximab for Rheumatoid Arthritis: A Retrospective Multicenter Italian Study.

OBJECTIVE: Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc-positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis. METHODS: Thirty-three HBsAg-negative/anti-HBc-positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1-8) over 34 months (range 0-80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated. RESULTS: None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs-negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0-70) after RTX discontinuation, no HBV reactivation was observed. CONCLUSION: The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.