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Aims: Data regarding the treatment of hip osteoarthritis (OA) with collagen-based extracellular bio-scaffolds are lacking. We evaluated the treatment of hip OA with ultrasound guided intraarticular injections of Collagen-based Medical Device (CMD)., Material and Methods: Forty-four patients with Kellgren-Lawrence grade (KLG) I or II were selected, and 20/44 randomly selected patients (CMD group), were treated with 2 weekly consecutive ultrasound guided intraarticular injections of CMD (MD-HIP, Guna S.p.a. Milan, Italy). An additional 24/44 patients were treated with oral non-steroidal anti-inflammatory drugs (NSAIDs) daily (NSAIDs group). Clinical assessment, X-rays and ultrasound evaluation were performed at baseline, and after 1 month in both groups, and after 3 months in the CMD group. Outcome measures were general pain VAS (0-10), the whole WOMAC score, and the WOMAC specific subscores., Results: CMD and NSAIDs group were homogenous for age, gender, VAS pain and WOMAC scores. The CMD group had significant improvement of the VAS pain (p<0.0001), global WOMAC score (p<0.0001) and WOMAC function (p<0.0001) from baseline to the 1st month, with further improvement from the 1st to the 3rd month (p<0,001; p<0.01; p<0.03, respectively). Significant improvement in WOMAC pain (p<0.0001) and WOMAC stiffness (p<0.0001) was detected at 1st month, with no significant change at 3rd month. In the NSAIDs group significant improvement in WOMAC function was detected after 1 month (p=0.021) only. No adverse events were recorded in the CMD and NSAIDs group., Conclusion: The ultrasound guided intraarticular hip injections of CMD resulted in significant improvement in VAS pain and WOMAC scores compared to treatment with oral NSAIDs.

Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD., Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t 0 ) and after 12 (±4) (t 1 ) and 24 (±4) (t 2 ) months., Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t 2 . Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t 2 ( p = 0.0031). Neither the mean t 0 to t 1 change (Δ) of DLCO nor the mean t 0 to t 1 FVCΔ predicted the appearance of ILD at t 2 . Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t 0 DLCO < 80%, stronger than that of FVC < 80%., Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Purpose: Capecitabine-Temozolomide (CapTem) is an oral chemotherapy regimen for NETs. Both drugs are radiosensitizers. Integrating CapTem and Y90 transarterial radioembolization (TARE) in patients with grade 2 neuroendocrine tumor (NET) liver metastases achieved an encouraging objective response rate (ORR) and progression-free survival (PFS) in a feasibility study. This study expands that report to a larger cohort with longer follow-up., Methods: Therapy consisted of monthly cycles of capecitabine 600 mg/m 2 twice daily for 14 days and temozolomide 150-200 mg/m2 on day 10-14. Simulation angiography was performed during the initial cycle. The dominant lobe was treated with 90 Y-resin microspheres using BSA dosimetry on day 7 of the second cycle of CapTem. Patients with bilobar disease had the other lobe treated on day 7 of the third or fourth cycle. CapTem was continued until progression or intolerance. Clinical and laboratory assessment was done monthly and imaging every 3 months., Results: 35/37 patients completed the prescribed regimen. Primary sites of disease were pancreas (16), lung (10), gut (7) and unknown (4). Mean duration of CapTem was 12 months (range, 4-32 months). ORR in the liver was 72% with a disease control rate of 100%. Median PFS was 36 months (95% CI, 25-45 months). Median overall survival was 41 months (95% CI, 24-87 months) from initiation of CapTemY90 therapy and 130 months (95% CI, 56-172 months) from initial diagnosis., Conclusion: Chemoradiation with CapTem and TARE provided durable control of G2 NET liver metastases for substantially longer than expectations for embolotherapy or chemotherapy alone., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Objective: This study was performed to assess the impact of autologous conditioned serum (ACS) when added to preceding intra-articular glucocorticoid therapy on pain, function, and quality of life outcomes over 24 weeks., Methods: In this single-center, randomized controlled trial involving 40 patients with advanced knee osteoarthritis (Kellgren-Lawrence grades III and IV), ACS or saline placebo was injected after 40 mg triamcinolone acetonide (TA) intra-articular injection. Numerical rating scale (NRS) pain scores and Knee Injury and Osteoarthritis Outcome Score (KOOS) assessments were conducted at baseline and at weeks 3, 6, 12, and 24. The primary endpoint was the change in KOOS Pain at 24 weeks. Patient safety events were also monitored., Results: At week 24, TA + ACS significantly improved KOOS Pain, Symptoms, Activities of Daily Living, Quality of Life, and KOOS Sport scores. TA + ACS also outperformed TA + placebo in NRS pain scores (average and maximum intensity) at week 24 and NRS pain score (at rest) at weeks 12 and 24. The TA injection followed by ACS or placebo was well-tolerated., Conclusion: ACS adds long-term pain relief and functional improvement to the short-term pain relief provided by glucocorticoids.

Purpose: Telegenetics services can expand access to guideline-recommended cancer genetic testing. However, access is often not distributed equitably to all races and ethnicities. We evaluated the impact of an on-site nurse-led cancer genetics service in a diverse Veterans Affairs Medical Center (VAMC) oncology clinic on likelihood of germline testing (GT) completion., Methods: We conducted an observational retrospective cohort study of patients who were referred for cancer genetics services at the Philadelphia VAMC between October 1, 2020, and February 28, 2022. We evaluated the association between genetics service (on-site v telegenetics) and likelihood of GT completion in a subcohort of new consults, excluding patients with prior consults and those referred for known history of germline mutations., Results: A total of 238 Veterans, including 108 (45%) seen on site, were identified for cancer genetics services during the study period, with the majority referred for a personal (65%) or family (26%) history of cancer. In the subcohort of new consults, 121 Veterans (54% self-identified race/ethnicity [SIRE]-Black), including 60 (50%) seen on site, were included in the analysis of germline genetic testing completion. In a univariate analysis, patients who were seen by the on-site genetics service had 3.2-fold higher likelihood of completing GT (relative risk, 3.22; 95% CI, 1.89 to 5.48) compared with the telegenetics service. In multivariable regression analysis, the on-site genetics service was associated with higher likelihood of GT completion, but this association was only statistically significant in SIRE-Black compared with SIRE-White Veterans (adjusted RR, 4.78; 95% CI, 1.53 to 14.96; P < .001; P -interaction of race × genetics service = .016)., Conclusion: An on-site nurse-led cancer genetics service embedded in a VAMC Oncology practice was associated with higher likelihood of germline genetic testing completion than a telegenetics service among self-identified Black Veterans.

Importance: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc., Objective: To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database., Design, Setting, and Participants: This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023., Main Outcomes and Measures: Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers)., Results: Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P < .001; and 68.3% in dcSSc; P < .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P < .001; and 87.6% in dcSSc; P < .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P = .03) but significantly higher in dcSSc (75.0%; P < .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P < .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti-Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P = .06) and dcSSc (55.5%; P < .001) after up to 15 years of follow-up., Conclusions and Relevance: Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.

Background: This study investigated the ability of patients, naïve to adalimumab treatment and self-injection with an autoinjector (AI), to successfully self-administer AVT02, an adalimumab biosimilar, using a custom, ergonomic AI (Alvotech hf., Reykjavik, Iceland)., Research Design and Methods: This was a single-arm, open-label study, consisting of an 8-week active period and 48-week extension phase. Patients with moderate to severe rheumatoid arthritis (RA) self-administered 40 mg AVT02 subcutaneously via AI in the active period, followed by prefilled syringe in the extension phase. The primary endpoint was the percentage of successful self-injections up to Week 8. Usability and robustness of the AI were evaluated in the active period; safety, efficacy, pharmacokinetic and immunogenicity data were assessed throughout the study., Results: The AI success rate was 100%. No handling events were noted up to Week 8. Both C trough measurements and immunogenicity profile were in line with expectations from previous studies, with no unexpected safety signals., Conclusions: This study demonstrated that AVT02-AI can be successfully and reliably used for repeated self-injections of AVT02 by moderate to severe RA patients, despite no previous experience of adalimumab self-administration. The extension phase provides long-term efficacy and safety data for AVT02 in RA., Study Identifier: NCT04224194.

Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between MTHFR rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions.

Objectives: The aim of this work was to determine hand joint inflammation in systemic sclerosis (SSc); patients with rheumatoid arthritis (RA) with hand joint involvement were used as controls. Our investigation also aimed at examining the relationship between these subclinical inflammatory changes in the hands, verified by low-frequency MRI, and clinical (especially cardiopulmonary) manifestations, disease activity, and functional capacity in patients with diffuse cutaneous (dcSSc) and limited cutaneous SSc (lcSSc). Methods: Out of 250 SSc patients, the selection included 82 patients with signs and symptoms of joint involvement, and 35 consecutive RA patients. These patients underwent clinical and laboratory investigations, and hand X-ray and MRI of the dominant hand. Synovitis/tenosynovitis, bone edema, and erosions were investigated, and the bone changes were quantified and scored using the RAMRIS method. HAQ index, modified Rodnan skin score, examination of internal organ involvement, and serological markers for SSc, as well as rheumatoid factor (RF) and cyclic citrullinated peptides antibodies (ACPA), were performed on all experimental group subjects. Results: MRI of the dominant hand showed a significantly higher number of cases with synovitis (78%) than the number of patients with clinically swollen joints (17.1%; p < 0.001); bone edema was found in 62 (75.6%) SSc patients. MRI also showed a higher number of erosions (52; 63.4%) compared to those (22; 27.5%) detected with X-ray (p < 0.001). The average values of the total MRI score of synovitis/edema and erosions in the wrist (p < 0.001) and MCP joints (p < 0.001) were statistically higher in RA than in SSc patients (p < 0.001). The probability of the MRI-detected inflammatory changes was considerably higher in SSc patients who had vascular complications (digital ulceration, OR = 4.68; 95% IP: 1.002−22.25; p < 0.05), in patients with more severe functional impairment (OR = 8.22; 95% IP: 1.74−38.89; p < 0.01), and in patients with active disease (OR = 3.132; 95% IP: 1.027−9.551; p < 0.05). In our investigation, patients with a limited form of the disease and with inflammatory changes on MR more often had higher functional impairment compared to the other group without MRI inflammation. Conclusions: Our data show that in SSc MRI can detect a significant subclinical joint inflammation. RAMRIS confirmed the high degree of joint inflammation in RA, but also revealed a great deal of joint inflammation in SSc. That inflammation is associated with systemic inflammation (disease activity), vascular complications, and more severe forms of the disease, as synovitis cannot be precisely diagnosed by the clinical examination of joints. These results suggest that a careful joint investigation is necessary in SSc, and that in symptomatic patients, MRI may identify joint inflammation. In clinical practice, this evidence might drive to an early targeted therapy, thus preventing joint erosions.

Background: Fluoropyrimidines (fluorouracil [5-FU], capecitabine) and irinotecan are commonly prescribed chemotherapy agents for gastrointestinal (GI) malignancies. Pharmacogenetic (PGx) testing for germline DPYD and UGT1A1 variants associated with reduced enzyme activity holds the potential to identify patients at high risk for severe chemotherapy-induced toxicity. Slow adoption of PGx testing in routine clinical care is due to implementation barriers, including long test turnaround times, lack of integration in the electronic health record (EHR), and ambiguity in test cost coverage. We sought to establish PGx testing in our health system following the Exploration, Preparation, Implementation, Sustainment (EPIS) framework as a guide. Our implementation study aims to address barriers to PGx testing., Methods: The Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI) study is a non-randomized, pragmatic, open-label implementation study at three sites within a major academic health system. Eligible patients with a GI malignancy indicated for treatment with 5-FU, capecitabine, or irinotecan will undergo PGx testing prior to chemotherapy initiation. Specimens will be sent to an academic clinical laboratory followed by return of results in the EHR with appropriate clinical decision support for the care team. We hypothesize that the availability of a rapid turnaround PGx test with specific dosing recommendations will increase PGx test utilization to guide pharmacotherapy decisions and improve patient safety outcomes. Primary implementation endpoints are feasibility, fidelity, and penetrance. Exploratory analyses for clinical effectiveness of genotyping will include assessing grade ≥3 treatment-related toxicity using available clinical data, patient-reported outcomes, and quality of life measures., Conclusion: We describe the formative work conducted to prepare our health system for DPYD and UGT1A1 testing. Our prospective implementation study will evaluate the clinical implementation of this testing program and create the infrastructure necessary to ensure sustainability of PGx testing in our health system. The results of this study may help other institutions interested in implementing PGx testing in oncology care., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04736472, identifier [NCT04736472]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Varughese, Bhupathiraju, Hoffecker, Terek, Harr, Hakonarson, Cambareri, Marini, Landgraf, Chen, Kanter, Lau-Min, Massa, Damjanov, Reddy, Oyer, Teitelbaum and Tuteja.)

Objective: To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease., Methods: We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored., Results: Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged ( P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0-1.1 and OR 1.2, 95% CI 1.1-1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs., Conclusion: Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc., (Copyright © 2022 by the Journal of Rheumatology.)

TGFβ is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFβ enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFβ inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients ( n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8 + PD-1 + TIGIT + T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression., (©2020 American Association for Cancer Research.)

Background and Aim: Striving for harmonisation of specialty training and excellence of care in rheumatology, the European League Against Rheumatism (EULAR) established a task force to develop points to consider (PtCs) for the assessment of competences during rheumatology specialty training., Methods: A systematic literature review on the performance of methods for the assessment of competences in rheumatology specialty training was conducted. This was followed by focus groups in five selected countries to gather information on assessment practices and priorities. Combining the collected evidence with expert opinion, the PtCs were formulated by the multidisciplinary task force, including rheumatologists, medical educationalists, and people with rheumatic and musculoskeletal diseases. The level of agreement (LoA) for each PtC was anonymously voted online., Results: Four overarching principles and 10 PtCs were formulated. The overarching principles highlighted the importance of assessments being closely linked to the rheumatology training programme and protecting sufficient time and resources to ensure effective implementation. In the PtCs, two were related to overall assessment strategy (PtCs 1 and 5); three focused on formative assessment and portfolio (PtCs 2-4); three focused on the assessment of knowledge, skills or professionalism (PtCs 6-8); one focused on trainees at risk of failure (PtC 9); and one focused on training the trainers (PtC 10). The LoA (0-10) ranged from 8.75 to 9.9., Conclusion: These EULAR PtCs provide European guidance on assessment methods throughout rheumatology training programmes. These can be used to benchmark current practices and to develop future strategies, thereby fostering continuous improvement in rheumatology learning and, ultimately, in patient care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Lessons Learned: Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers. Further clinical evaluation of palbociclib monotherapy is not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches., Background: Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy., Methods: Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1-21 of 28-day cycles. The primary endpoint was overall response rate., Results: We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression-free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%)., Conclusion: Palbociclib has limited single-agent activity in gastroesophageal tumors., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy - DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecan - and the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic., (© 2020 Pharmacotherapy Publications, Inc.)

Background: In the randomized, phase III, global SELECT-COMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients., Methods: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted., Results: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks., Conclusion: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks., Competing Interests: Disclosure and potential conflicts of interest: Karel Pavelka has received honoraria from AbbVie, Amgen, BMS, Egis, Hospira, Medac, MSD, Pfizer, Roche, and UCB. Zoltán Szekanecz has received consulting fees and honoraria from AbbVie, Amgen, BMS, Gedeon Richter, Lilly, MSD, Pfizer, Roche, Sanofi, and UCB. Nemanja Damjanov has received grants and research support from AbbVie, Pfizer, and Roche, and consulting fees and honoraria from AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche. Branimir Anić has nothing to disclose. Matija Tomšič has received research grants, consulting fees, and honoraria from AbbVie, Amgen, Biogen, Celltrion, Lilly, Novartis, Pfizer, Roche, and Sanofi. Vadim Mazurov has nothing to disclose. Marija Maksimovic and Orsolya Nagy are employees of AbbVie Ltd and may own AbbVie stock. Jerzy Świerkot has received honoraria from AbbVie, Amgen, BMS, Egis, Gedeon Richter, Lilly, MSD, Pfizer, Roche, Novartis, and UCB. Tzvetanka Petranova has received consulting fees and honoraria from AbbVie, Amgen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB. Tiina Veldi has nothing to disclose. Asta Baranauskaitė has received research funding, consulting fees, and honoraria from AbbVie. Catalin Codreanu has received consulting fees and honoraria from AbbVie, Amgen, BMS, Egis, MSD, Pfizer, Roche, Sanofi, and UCB. Daina Andersone has received grants and consulting fees from AbbVie, Amgen, BMS, Janssen, Novartis, Pfizer, and Roche. Roy Fleischmann has received grants and consulting fees from AbbVie, Amgen, BMS, Gilead, Lilly, Novartis, and Pfizer, and grants from EMD-Serono, Genentech, Roche, Sanofi, and UCB. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2020/09/dic.2020-7-5-COI.pdf, (Copyright © 2020 Pavelka K, Szekanecz Z, Damjanov N, Anić B, Tomšič M, Mazurov V, Maksimovic M, Nagy O, Jerzy Świerkot J, Petranova T, Veldi T, Asta Baranauskaitė A, Codreanu C, Andersone D, Fleischmann R.)

Objective: To evaluate the efficacy and safety of PF-06651600 (ritlecitinib), an irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, in comparison with placebo in patients with rheumatoid arthritis (RA)., Methods: An 8-week, phase II, double-blind, parallel-group study was conducted. Seventy patients who were seropositive for anti-citrullinated protein antibodies and/or rheumatoid factor were randomized 3:2 to receive oral PF-06651600 (200 mg once daily) or placebo for 8 weeks. Eligible patients had an inadequate response to methotrexate, and the study design allowed up to 50% of patients to have previously received 1 tumor necrosis factor inhibitor that was inadequately effective and/or not tolerated. The primary end point was change from baseline in the Simplified Disease Activity Index (SDAI) score at week 8, assessed by Bayesian analysis using an informative prior distribution for placebo response., Results: Mean change from baseline in the SDAI score at week 8 was greater in the PF-06651600 group (-26.1 [95% credible interval -29.7, -22.4]) than in the placebo group (-16.8 [95% credible interval -20.9, -12.7]; P < 0.001). Most adverse events (AEs) were mild in severity, and no treatment-related serious AEs, severe AEs, or deaths were reported. The most common classes of AE were infections and infestations as well as skin and subcutaneous tissue disorders; there was 1 mild case of herpes simplex in the PF-06651600 group that was considered to be treatment related, which resolved within 3 days without study treatment discontinuation or antiviral therapy., Conclusion: Treatment with the oral JAK3/TEC inhibitor PF-06651600 (200 mg once daily) was associated with significant improvements in RA disease activity and was generally well-tolerated in this small 8-week study., (© 2020 Pfizer Inc. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: The aim of this study was to evaluate chemosensory function and oral disorders in patients with primary Sjögren's syndrome (pSS) and to compare these findings with those of age- and gender-matched healthy controls., Methods: This comparative cross-sectional study included 58 patients with primary Sjögren's syndrome (pSS) and 55 age- and gender-matched healthy controls. Olfactory and gustatory function, burning sensations in the tongue (BST) and halitosis were assessed. Oral health-related quality of life (OHRQoL) was evaluated using the short-form Oral Health Impact Profile (OHIP-14)., Results: Patients with pSS had significantly lower self-reported visual analogue scale (VAS) smell score (8.6 ± 2.2 vs. 9.6 ± 0.7, p = 0.016) and VAS taste score (8.5 ± 2.1 vs. 9.5 ± 0.7, p = 0.014) than healthy controls. A greater proportion of patients with pSS had anosmia (3.8% vs. 0.0%) or hyposmia (36.5% vs. 13.2%) and ageusia for basic tastes: sweetness (34.0% vs. 7.5%), sourness (10.6% vs. 0.0), saltiness (10.0% vs. 5.7%) or bitterness (19.1% vs. 1.9%) as evaluated using Sniffin Sticks test and taste stripts, respectively. A higher proportion of pSS patients complained of dysgeusia (52.6% vs. 9.4%, p < 0.0001) and BST (45.6% vs. 0.0%, p < 0.0001), while similar number of patients with pSS and controls reported halitosis (31.6% vs. 28.3%, p = 0.434). The mean OHIP-14 score was significantly higher in patients with pSS (6.8 ± 7.0 vs. 2.3 ± 8.5, p < 0.001) indicating patients' poorer OHRQoL compared with controls., Conclusions: The majority of patients with pSS had impaired chemosensory function and indicators of oral health in comparison with the age- and gender-matched healthy controls. Further studies of oral hygiene habits and dietary intake of these patients are needed to ensure better management of oral health problems in patients with pSS.

Objective: High frequency ultrasound allows visualization of epidermis, dermis and hypodermis, precise measurement of skin thickness, as well as assessment of skin oedema, fibrosis and atrophy. The aim of this pilot cross-sectional observational study was to assess the performance and multiobserver variability of ultra-high-frequency (UHF) (50 MHz) ultrasound (US) in measuring skin thickness as well as the capacity of UHF-derived skin features to differentiate SSc patients from healthy controls., Methods: Twenty-one SSc patients (16 limited and five diffuse SSc) and six healthy controls were enrolled. All subjects underwent US evaluation by three experts at three anatomical sites (forearm, hand and finger). Dermal thickness was measured and two rectangular regions of interest, one in dermis and one in hypodermis, were established for texture feature analysis., Results: UHF-US allowed a precise identification and measurement of the thickness of the dermis. The dermal thickness in the finger was significantly higher in patients than in controls (P < 0.05), while in the forearm it was significantly lower in patients than in controls (P < 0.001). Interobserver variability for dermal thickness was good to excellent [forearm intraclass correlation coefficient (ICC) = 0.754; finger ICC = 0.699; hand ICC = 0.602]. Texture computed analysis of dermis and hypodermis was able to discriminate between SSc and healthy subjects (area under the curve >0.7)., Conclusion: These preliminary data show that skin UHF-US allows a very detailed imaging of skin layers, a reliable measurement of dermal thickness, and a discriminative capacity between dermis and hypodermis texture features in SSc and healthy subjects., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations., Methods: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses., Results: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]., Conclusion: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate fenebrutinib, an oral and highly selective non-covalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA)., Methods: Patients with RA and inadequate response to methotrexate (cohort 1, n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200 mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued methotrexate therapy., Results: In cohort 1, American College of Rheumatology scores (ACR50) at week 12 were similar for fenebrutinib 50 mg once daily and placebo, and higher for fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo (15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most common adverse events for fenebrutinib included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers., Conclusion: Fenebrutinib demonstrated efficacy comparable to adalimumab in patients with an inadequate response to methotrexate, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA., (This article is protected by copyright. All rights reserved.)

Capillaroscopy is a non-invasive and safe tool which allows the evaluation of the morphology of the microcirculation. Since its recent incorporation in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis together with its assessed role to monitor disease progression, capillaroscopy became a 'mainstream' investigation for rheumatologists. Given its increasing use by a variety of physicians internationally both in daily practice to differentiate primary from secondary Raynaud's phenomenon, as well as in research context to predict disease progression and monitor treatment effects, standardisation in capillaroscopic image acquisition and analysis seems paramount. To step forward to this need, experts in the field of capillaroscopy/microcirculation provide in this very consensus paper their view on image acquisition and analysis, different capillaroscopic techniques, normal and abnormal capillaroscopic characteristics and their meaning, scoring systems and reliability of image acquisition and interpretation., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aims to assess the possible relationship between 99m Tc-pertechnetate hand perfusion scintigraphy (HPS) and nailfold capillaroscopy (NC) in systemic sclerosis (SSc) patients., Patients and Methods: The study group consisted of 25 SSc patients (6 males; 19 females; mean age 54.2±9.7 years; range, 32 to 67 years), 18 female patients with primary Raynaud's phenomenon (PRP) (mean age 47.1±9.5 years; range, 34 to 65 years) and 10 healthy individuals (3 males, 7 females; mean age 52.7±12.6 years; range, 37 to 73 years). NC and 99m Tc-pertechnetate HPS were performed in all examinees. The capillaroscopic findings were classified as normal or scleroderma pattern ("early", "active", or "late"). The fingers-to-palm ratios were calculated for both blood flow (BF) and blood pool (BP) phases of the 99m Tc-pertechnetate HPS., Results: Systemic sclerosis patients showed a significantly lower BP ratio than PRP patients and healthy subjects (p=0.004). No statistically significant difference was observed between the SSc and PRP patients in respect to BF ratio. A gradual decrease of BF and BP with the severity of NC microangiopathy pattern ("early", "active" or "late") was found in SSc patients, while the differences were not statistically significant. Patients with diffuse SSc showed lower BF and higher BP than those with limited SSc, while these differences were without statistical significance. There was no significant correlation between BF or BP values and type of SSc (limited or diffuse) (p=0.77 versus p=0.54, respectively) as well as three microangiopathy patterns (p=0.22 versus p=0.54, respectively)., Conclusion: 99m Tc-pertechnetate HPS improves the evaluation of vascular damage in SSc patients. There is no direct relationship between NC and 99m Tc-pertechnetate HPS; however, the two methods complement each other in the assessment of microcirculation in SSc., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2020, Turkish League Against Rheumatism.)

Systemic sclerosis is the main systemic fibrotic disease with unknown etiology characterized by peripheral microvascular injury, activation of immune system, and wide-spread progressive fibrosis. Microparticles can be derived from any cell type during normal cellular differentiation, senescence, and apoptosis, and also upon cellular activation. Carrying along a broad range of surface cytoplasmic and nuclear molecules of originating cells, microparticles are closely implicated in inflammation, thrombosis, angiogenesis, and immunopathogenesis. Recently, microparticles have been proposed as biomarkers of endothelial injury, which is the primary event in the genesis of tissue fibrosis. Microparticles may have a role in fostering endothelial to mesenchymal transition, thus giving a significant contribution to the development of myofibroblasts, the most important final effectors responsible for tissue fibrosis and fibroproliferative vasculopathy. Thanks to potent profibrotic mediators, such as transforming growth factor beta, platelet-derived growth factor, high mobility group box 1 protein, nicotinamide adenine dinucleotide phosphate oxidase 4, and antifibrotic agents, such as matrix metalloproteinases, microparticles may play an opposite role in fibrosis., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Objectives: To assess the association between salivary ultrasonography (sUS) findings and disease activity and damage in patients with primary Sjogren's syndrome (pSS). We investigated the potential prognostic role of sUS as a tool in the assessment of disease activity., Methods: In 303 pSS patients, disease activity was assessed by the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), the Sjogren's Syndrome Disease Activity Index (SSDAI) and the Sjogren's Syndrome Disease Damage Index (SSDDI). The sUS parenchymal inhomogeneity (de Vita scoring system) was assessed in 303 pSS patients and 111 heathy controls. A receiver operating characteristic (ROC) curve was used to determine the cut-off value of the pathological sUS score. Logistic regression analysis was performed to assess risk factors for moderate and high disease activity., Results: A pathological sUS score ≥ 2 was recorded in 271 (89.7%) patients and 8 (8.6%) healthy controls. Patients with moderate and high ESSDAI and SSDAI scores had significantly higher US activity in comparison to that of pSS patients with low disease activity (p = 0.006; p = 0.01, respectively). Additionally, pSS patients with moderate and high SSDDI scores had higher US activity (p = 0.031). Pathological sUS correlated with the glandular domain within the ESSDAI and SSDDI (p<0.001). The patients with a severe US score (5-6) had a 3.5 times greater chance of having moderate or high disease activity. The specificity of the severe de Vita sUS score for ESSDAI and SSDAI was 85.1% and 85.2%, respectively. In contrast, the sensitivity of a severe de Vita sUS score for ESSDAI was low, at 29.2%, while the sensitivity for the SSDAI was higher, 42.3%. In the analysis of disease activity, a de Vita score ≥ 5 could be used as a risk factor for moderate and high ESSDAI (p = 0.042) and SSDAI (p = 0.006)., Conclusions: Pathological salivary gland ultrasonography is associated with high disease activity and damage in pSS. Consequently, sUS abnormalities might be surrogate items for glandular domains in the assessment of disease activity and damage. Thus, ultrasonography of the salivary gland combined with clinical and serological markers might be part of the next prognostic and therapeutic algorithm in the near future., Competing Interests: The authors have declared that no competing interests exist.

Background: In this work, we aimed to establish a clinical target in the management of knee osteoarthritis (KOA) and to propose good clinical practice (GCP) statements for carrying out a treat-to-target strategy., Methods: A steering committee of seven experts had formulated a provisional set of recommendations that were exposed for discussion and modification to a technical expert panel (TEP) of 25 multidisciplinary experts from Europe, North America, South America and Asia. The level of evidence and strength of each recommendation was discussed. The TEP formulated overarching principles and GCP statements based on the level of agreement for each item with a vote using a 10-point numerical scale., Results: Two overarching principles and 10 GCP statements were formulated by the TEP. These GCP statements suggest: treatment should achieve clinical improvement bringing the patient to the Patient Acceptable Symptom State (PASS); pharmacological and nonpharmacological treatment should begin as early as possible, with an early diagnosis of symptomatic KOA; the patient should be evaluated every 3-6 months; risk factors of KOA progression should be identified and managed with patients at the beginning of the treatment and monitored regularly; treatment should be adapted according to patient phenotype and disease severity; healthy lifestyle must be promoted and monitored. The level of agreement average ranged from 8.7 to 9.6 on scale., Conclusions: The proposed overarching principles and GCP statements have the aim of involving patients, general practitioners and multidisciplinary specialists in sharing a therapeutic treat-to-target strategy for KOA management based on the best evidence and expert opinions., Competing Interests: Conflict of interest statement: Abiogen Pharma Spa supported all the costs of the meeting of the authors, including travel and subsistence. No honoraria were paid to the participants. Abiogen Pharma Spa had no input in the writing or editing of the paper., (© The Author(s), 2019.)

Objectives: To develop and test the reliability of a new semiquantitative scoring system for the assessment of cartilage changes by ultrasound in a web-based exercise as well as a patient exercise of patients with RA., Methods: A taskforce of the Outcome Measures in Rheumatology Ultrasound Working Group performed a systematic literature review on the US assessment of cartilage in RA, followed by a Delphi survey on cartilage changes and a new semiquantitative US scoring system, and finally a web-based exercise as well as a patient exercise. For the web-based exercise, taskforce members scored a dataset of anonymized static images of MCP joints in RA patients and healthy controls, which also contained duplicate images. Subsequently, 12 taskforce members used the same US to score cartilage in MCP and proximal interphalangeal joints of six patients with RA in in a patient reliability exercise. Percentage agreement and prevalence of lesions were calculated, as intrareader reliability was assessed by weighted kappa and interreader reliability by Light's kappa., Results: The three-grade semiquantitative scoring system demonstrated excellent intrareader reliability (kappa: 0.87 and 0.83) in the web-based exercise and the patient exercise, respectively. Interreader reliability was good in the web-based exercise (kappa: 0.64) and moderate (kappa: 0.48) in the patient exercise., Conclusion: Our study demonstrates that ultrasound is a reliable tool for evaluating cartilage changes in the MCP joints of patients with RA and supports further development of a new reliable semiquantitative ultrasound scoring system for evaluating cartilage involvement in RA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To assess prevalence and change of depression/anxiety symptoms in spondyloarthritis patients and feasibility of depression/anxiety questionnaires. 43 Patients with axial spondyloarthritis (axSpA) and 27 patients with psoriatic arthritis (PsA) were consecutively recruited. There were 34 patients on biologics and 36 patients on nonbiologics. Patients were not previously treated for depression. The demographic variables, pain, patient global assessment, laboratory, clinical findings, diseases activity scores, Beck Depression Inventory (BDI) and Depression Anxiety and Stress Scale-short version (DASS-21) were collected. The study visits were at the beginning, after 1 month, after 3 and after 6 months. In axSpA and PsA patients on biologics, BDI and DASS-21 were significantly lower compared to nonbiologics group during time. The axSpA patients on biologics had significantly lower BDI and depression severity by BDI at each time point and lower DASS-21 after 1, 3 and 6 months. BDI in PsA patients who received biological therapy was significantly lower after 3 and 6 months. In biologics groups, BDI significantly decreased after 3 months in axSpA patients and after 1 month in PsA patients. In axSpA patients, there was a medium correlation between BDI and axial pain, patient global assessment and disease activity scores. The biological therapy significantly affected the depression/anxiety symptoms in axSpA and PsA during time. BDI moderately correlated with pain and disease activity in axSpA. BDI and DASS-21 are easy to use in daily practice.

Background: Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate., Methods: SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of of upadacitinib or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951., Findings: Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35-48) in the continued methotrexate group, 147 (68%) of 217 patients (62-74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65-77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14-25) in the continued methotrexate group, 97 (45%) of 217 (38-51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46-60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study., Interpretation: Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies., Funding: AbbVie Inc, USA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches., Methods: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression., Results: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss., Conclusion: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS., (Published by Oxford University Press 2018.)

Hepatocellular carcinoma (HCC) is a challenging to treat malignancy with few available systemic therapies. Angiogenesis has been implicated in the pathogenesis of HCC and prior studies have suggested a role for anti-VEGF therapy. Prior to FDA approval of second-line therapy for advanced HCC, from 2008 until 2017, we initiated bevacizumab monotherapy (5-10 mg/kg every 2-3 weeks) in 12 patients with intolerance of or progression during sorafenib therapy. Bevacizumab therapy was well tolerated with only 1/12 patients experiencing a grade 3-4 treatment-related adverse event (transient ischemic attack) and only 2/12 patients discontinued the therapy due to adverse events. Median overall survival was 20.2 months (IQR, 7.0-43.5), with a median time to radiologic progression of 10.4 months (IQR, 2.8-16.1) and a disease control rate of 54%. Taken together, our experience provides rationale for further prospective investigation of bevacizumab for the treatment of advanced HCC., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To evaluate the level of agreement on ultrasonographic (US) lesions among highly experienced sonographers as well as the intraobserver and interobserver reliability of inflammatory and structural US lesions in patients with osteoarthritis (OA) of the foot., Methods: After a systematic literature review, a Delphi survey was performed to test definitions of US lesions in OA of the foot, including inflammatory lesions (ie, synovial hypertrophy [SH], joint effusion [JE], power Doppler signal [PD]), and structural abnormalities (ie, cartilage damage [CD] and osteophytes). Subsequently, the reliability of US in assessing the aforementioned lesions was tested on static images as well as during a live exercise. Reliability was assessed by kappa analyses and prevalence-adjusted bias-adjusted kappa (PABAK) on a dichotomous and an ordinal scale., Results: Intraobserver and interobserver reliability for SH and JE evaluated by binary scoring was good for both components, while the intraobserver reliability for semiquantitative scoring of SH ranged from moderate in the web-based exercise (PABAK 0.49) to good (PABAK 0.8) in the live exercise. Reliability for CD and PD assessments were respectively good and excellent in all exercises (ranged from PABAK 0.61 to 0.79 for CD and 0.88 to 0.95 for PD). The interobserver reliability for the semiquantitative scoring of osteophytes was fair in the live exercise (PABAK 0.36) and moderate in the static exercise (PABAK 0.60)., Conclusions: Consensual US definitions were found to be reliable for assessing inflammatory lesions in OA of the foot, while the use of US to assess structural damage requires further studies., Competing Interests: Competing interests: None declared.