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Copyright of Acta Reumatológica Portuguesa is the property of Sociedade Portuguesa de Reumatologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Acta Reumatológica Portuguesa is the property of Sociedade Portuguesa de Reumatologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The representation of metabolic reactions strongly relies on visualization, which is a major barrier for blind users. The NavMol software renders the communication and interpretation of molecular structures and reactions accessible by integrating chemoinformatics and assistive technology. NavMol 3.0 provides a molecular editor for metabolic reactions. The user can start with templates of reactions and build from such cores. Atom-to-atom mapping enables changes in the reactants to be reflected in the products (and vice-versa) and the reaction centres to be automatically identified. Blind users can easily interact with the software using the keyboard and textto- speech technology. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is characterized by synovitis of multiple joints which if not properly treated can progress to joint destruction. When liver damage is present in RA patients, it may be difficult to determine if it is an hepatic manifestation of RA, if there is an associated primary liver disease or whether hepatotoxic liver disease developed during the treatment of RA. Primary biliary cholangitis (PBC) is an autoimmune disease of the liver of unknown origin. It is characterized by inflammation and destruction of intrahepatic bile ducts, resulting in progressive cholestasis and, potentially, liver cirrhosis. About 1.8 - 5.6% of individuals with PBC have RA. Patients with RA are at higher risk of developing PBC compared to the general population. Objective: We report a case in which tocilizumab therapy was effective in the control of RA and PBC. Clinical Case: A 76-year-old man, previously diagnosed with PBC treated with ursodeoxycholic acid (UDCA), was observed in our Rheumatology department with symmetric and additive polyarthritis of small joints of the hands (metacarpophalangeal and proximal interphalangeal joints). Blood sample analysis revealed positive anti-citrullinated protein antibodies (ACPA) antibodies and rheumatoid factor along with increased inflammatory parameters, elevation of gamma glutamyltranspeptidase (5 times the upper limit of normal (ULN)) and alkaline phosphatase (2 times ULN). Plain hand radiographs showed erosions and ultrasound revealed synovitis of several metacarpophalangeal and interphalangeal proximal joints. The diagnosis of RA was established. Due to abnormal cholestasis blood markers it was decided to start only prednisolone 10mg/day, with clinical and analytical improvement. However, a relapse was observed with the reduction of corticoid dose. Introduction of conventional synthetic DMARDs was contraindicated due to the hepatic abnormalities. At this point, the rheumatologist and gastroenterologist's opinion was to start biological therapy in monotherapy and tocilizumab was chosen. With this treatment, the patient experienced significant clinical and analytical improvement, without new episodes of arthritis and with normalization of both inflammatory and hepatic cholestasis markers. Thus, prednisolone was progressively tapered and the patient maintained sustained remission of RA and PBC with tocilizumab and UDCA. Discussion: In RA, tocilizumab monotherapy was shown to be superior to methotrexate monotherapy. This was not observed with TNF-α inhibitors.5 Furthermore, autoimmune hepatitis incidence is increased with anti-TNF-α therapy.6 In PBC there is a deregulation of the T lymphocytes, with lymphoid infiltration in the portal ducts. In addition, local inflammation leads to the activation of mononuclear cells and production of IL-6 and others cytokines.7 This increase of IL-6 shown in PBC may justify tocilizumab good response in this clinical case. This case report, along with published literature 8 data suggests that tocilizumab may be effective and safe in the treatment of RA in patients with PBC. Inhibition of IL-6 seem to lead to normalization of inflammatory activity, which may also be effective in PBC treatment, but further studies will be necessary to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Copyright of Acta Reumatológica Portuguesa is the property of Sociedade Portuguesa de Reumatologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The association between cardiovascular (CV) risk and chronic systemic inflammatory diseases has been an issue of debate. There is compelling evidence of increased CV morbidity in conditions such rheumatoid arthritis (RA) and systemic lupus erythematous (SLE) (1). Primary Sjögren's syndrome (pSS) is a chronic immune-mediated disease characterized by glandular and systemic manifestations, sharing clinical and immunological similarities with RA and SLE. However, in pSS patients the weight of cardiovascular disease attributed to traditional CV risk factors remains unclear. Objectives: To determine the prevalence of traditio nal CV risk factors and long-term CV events based on the risk prediction tool of the Framingham risk score (FRS) in pSS patients. Methods: The study included patients diagnosed with pSS, fulfilling both the 2016 ACR/EULAR and 2002 AECG criteria for the disease, followed-up at our Rheumatology department and 49 age and sexmatched controls. Inclusion criteria were age 30 to 74 and no history of CV events in order to calculate the FRS. In total, 46 out of 54 patients were eligible for the study. Data on the prevalence of traditional CV risk factors (diabetes, arterial hypertension and smoking), systolic blood pressure (SBP) values, total and high-density lipoprotein (HDL) cholesterol levels were collected and compared between groups. The 10-year risk for CV events according to FRS was calculated and means of patients and controls were compared. Parametric and nonparametric tests were used and the level of significance was defined as p<0.05. Results: The mean age of pSS patients and healthy individuals was 58.0±11.6 and 54.1±13.6 years, respectively. The prevalence of arterial hypertension was hi - gher in pSS patients than controls (52.2% versus 24.5%, p=0.005). The prevalence of diabetes and smoking did not differ significantly between the two groups (p=0.674 and p=0.949, respectively). The SBP values, total and HDL cholesterol levels were also similar between pSS patients and healthy subjects (p=0.063, p=0.413 and p=0.217, respectively). Mean 10-years risk for CV events assessed by FRS was 11.8±8.3 for pSS patients and 7.8±8.4 for matched controls, with statistically significant difference (p=0.013). Conclusion: In our study, pSS patients had a higher prevalence of arterial hypertension, which is in agreement with the M. Juarez et al (1) study. Although there were no significant differences in the other traditional CV risk factors, the results showed an increased 10-year risk for major CV events based on FRS assessment in pSS patients in comparison to age and sex-matched controls. [ABSTRACT FROM AUTHOR]

An abstract of the article "Regiocontrolled SNAr Reaction on 2,3-Dihalopyridines with NaSMe to Obtain Bromo(methylthio)pyridines as Key Precursors of 3-Halo-2-(hetero)arylthieno[2,3-b]pyridines and Thieno[3,2-b]pyridines" by Agathe Begouin and colleagues is presented.

A simple, general, and efficient methodology for the synthesis of the title compounds is described for the first time. [ABSTRACT FROM AUTHOR]

Background: Access to pediatric rheumatology (PR) is not well described in Portugal. The main goal of this study was to ascertain barriers to PR referrals and subsequent alternative referral patterns among family doctors and pediatricians., Methods: A web-based survey was e-mailed to family doctors and pediatricians practicing in Portugal, in order to investigate access to PR care issues. Descriptive and comparative analysis was performed., Results: Two hundred and ninety-two responses were obtained, 24.7% from pediatricians and 75.3% from family doctors. Only 12% claimed to have had specific education on PR. Nearly 70% worked less than one hour away from a PR center. Twenty eight percent had referred a patient to PR at least once, and 9.3% experienced a situation in which they considered referring to PR but ultimately did not. Many referred to other specialties, primarily pediatrics, adult rheumatology, and pediatric orthopedics. Pediatricians encountered more diversified rheumatic diseases. Fifty five percent had no opinion on PR centers' support, while 24% found it sufficient. Having specific training on PR, being a pediatrician and a specialist were associated with greater referrals to PR. The most rated measure for PR referrals' improvement was promoting education. Regional access to PR's discrepancies were documented., Conclusion: Mainly lack of education on PR, but also uneven national coverage and greater distances to some PR centers were the main barriers to PR referrals, in Portugal. Pediatricians seem to have better education, greater experience and more referrals to PR. The current alternatives for referral are pediatrics, adult rheumatology and pediatric orthopedics. Educational consolidation was the biggest and most rewarding inconsistency to battle against.

Aim: To assess the predictive factors for a subsequent fragility fracture (FF) and mortality., Methods: Retrospective monocentric study including patients observed at the emergency department (ED) of a referral hospital with a FF, between 1st January 2017 and 31st December 2018. Fractures events were identified through discharge codes using the 9th International Classification of Diseases codes and FF were adjudicated after revision of the clinical files. We identified 1673 patients with FF. After calculating a representative sample (95% confidence interval), 172 hip, 173 wrist and 112 vertebral fractures were included in the analysis. Their clinical files were reviewed until 31st December 2020. A multivariate analysis was performed in order to identify predictive factors for FF., Results: Overall, during the follow-up period 76 patients (16.6%) had a new FF and 120 patients (26.3%) died. Multivariate analysis showed that previous visits to the ED due to falls (p=0.002) and malignancy (p=0.026) were independent risk factors for a new FF. The main predictors of mortality were age, hip fracture, oral corticosteroid treatment, normal or low BMI and cardiac, neurologic or chronic kidney disease., Conclusions: FF are a very prevalent public health problem that can lead to significant morbidity and death. Certain comorbidities seem to be associated with new FF and increased mortality. There might be a substantial missed opportunity for intervention in these patients, namely in ED visits.

Objective: To identify predictive factors of relapse after discontinuation of Methotrexate (MTX) in Juvenile Idiopathic Arthritis (JIA) patients with inactive disease., Methods: We conducted a prospective multicenter cohort study of patients diagnosed with JIA using real world data from the Portuguese national register database, Reuma.pt. Patients with JIA who have reached JADAS27 inactive disease and discontinued MTX before the age of 18 were evaluated., Results: A total of 1470 patients with JIA were registered in Reuma.pt. Of the 119 bionaive patients who discontinued MTX due to inactive disease, 32.8% have relapsed. Median time of persistence (using the Kaplan-Meier method and log-rank tests) with inactive disease was significantly higher in patients with more than two years of remission before MTX discontinuation and in those who did not use NSAIDs at time of MTX discontinuation. In Cox regression analyses and after adjustment for age at diagnosis, MTX tapering and JIA category, the use of NSAIDs at the time of MTX discontinuation (HR, 1.98 95%CI 1.03-3.82) and remission time of less than two years before suspension (HR, 3.12 95%CI 1.35-7.13) remained associated with relapse. No association was found between JIA category or the regimen of MTX discontinuation and the risk of relapse., Conclusions: In this large cohort we found that the use of NSAIDs at the time of MTX discontinuation was associated with a two times higher likelihood of relapse. In addition, longer duration of remission before MTX withdrawal reduces the chance of relapse in bionaive JIA patients.

Competing Interests: The authors declare no conflict of interest.

Competing Interests: The authors declare they have no conflicts of interest.

Abstract: More than 90% of septic arthritis cases are monoarticular. Joint infection can occur through several mechanisms such as hematogenous dissemination, by contiguity from adjacent infected soft tissue, surgical contamination, direct inoculation, or joint trauma.We report the case of a 69-year-old man admitted to our hospital with septic polyarthritis. The presented case is remarkable given its atypical presentation. The patient had no known risk factors for septic arthritis, comorbidities, or history of recurrent infections that could suggest some degree of immunosuppression. The atypical polyarticular involvement at presentation, the absence of sustained fever, and the good general condition of the patient delayed the diagnosis and treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Coexistence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and inflammatory bowel disease (IBD) is rare (Sy et al. in Semin Arthritis Rheum 45:475-482, 2016). Nevertheless, we present a case of an AAV in a 53-year-old female with enteropathic spondylarthritis previously treated with tumor necrosis factor α inhibitors (TNFi). Management of vasculitis in a patient with IBD may be problematic due to the difficulty in distinguishing if the vasculitis is an extraintestinal manifestation of the IBD or a new coexistent entity. Moreover, in our report, the previous treatment with TNFi is a possible confounding factor due to the paradoxical effects induced by TNFi, including vasculitis (Ramos-Casals et al. in Curr Rheumatol Rep 10:442-448, 2008). The reported case alerts to the complexity in the management of patients with enteropathic spondylarthritis and vasculitis, as well as discusses the diversity of differential diagnosis in this particular clinical scenario., (© 2021. International League of Associations for Rheumatology (ILAR).)

Osteoarthritis (OA) is frequently regarded by patients and health care providers as a normal consequence of ageing and a minor condition. In contrast, rheumatoid arthritis (RA) is a pathological condition that usually requires prolonged treatment and regular Rheumatology follow-up. Pain and physical limitations are hallmarks of both conditions and some previous studies suggest that OA and RA may have a similar burden for both groups of patients although those works usually do not take into account the inflammatory activity of RA. With this work, the authors compare levels of pain, physical disability and health-related quality of life in patients with primary hand osteoarthritis (hOA) and with RA - active disease (aRA) or in remission (rRA). The results show that hOA may have similar or even higher burden of pain than RA even with clinically relevant inflammatory activity in hand joints. Rather than suggesting that OA could be as severe as RA (or more or less severe), this brief study highlights OA as a cause of severe pain, which should lead us to try to achieve better symptom control for these patients and encourage rheumatologists to endeavor efforts to perform more studies in the field of OA.

Objective: To evaluate and describe the strategies of Portuguese rheumatologists and paediatricians, regarding either the maintenance or the withdrawal of classic and biologic disease-modifying anti-rheumatic drugs (cDMARDs and bDMARDs, respectively), when patients with Juvenile Idiopathic Arthritis (JIA) achieved clinical inactive disease (CID)., Methods: We performed a 30-question questionnaire, which was sent to all the 35 clinicians enrolled in the Portuguese group of paediatric rheumatology., Results: Twenty-three complete responses were obtained. The factors with the greatest impact on the decision to withdraw cDMARDs were: the duration of the CID, the therapy-induced toxicity, the presence of erosive disease and joint damage, the subtype of JIA, the time to reach inactive disease and the low adherence to therapy. These factors were classified as "very important" in this decision by more than 50% of the clinicians. The same factors, except for low adherence, had the greatest impact, when considering the withdrawal of bDMARDs. Withdrawal was more likely in patients with persistent oligoarticular JIA and less likely in rheumatoid factor positive polyarticular JIA. Sulfasalazine was more susceptible to be discontinued than methotrexate. Contrariwise, there were no differences concerning bDMARDs. Most participants reported that they started the drug withdrawal only after 12 months of sustained remission, by progressively tapering the dose of the cDMARD and spacing the intake of the bDMARD. Also, they reported that the decision to suspend the DMARD was based on imaging methods, preferably ultrasound, and in patient-reported outcomes. For patients on combination therapy, bDMARDs are reported to be the first to be withdrawn., Conclusions: Literature is scarce on this matter and there are no well-defined guidelines on how to withdrawal cDMARDs or bDMARDs on JIA. Notwithstanding, most Portuguese physicians were in agreement on the factors that needed to be taken into account with respect to the withdraw decision.

Introduction: Erasmus syndrome (ErS) is a rare entity in which Systemic Sclerosis (SSc) develops following exposure to silica, with or without associated silicosis. The objectives of this study were: 1) to evaluate the prevalence of ErS in our SSc cohort; 2) to characterize the cases; 3) to evaluate the clinical and laboratory characteristics of SSc in patients with (Ers) or without silica exposure., Methods: Cross-sectional and analytical study. Sociodemographic, clinical and laboratory data were collected from all patients with SSc diagnosed in our department according to ACR / EULAR criteria. Data on professional activity and possible exposure to silica were obtained by phone interview., Results: Among 48 patients with SSc, the prevalence of ErS was 16.7% (8/48). All cases identified were male, corresponding to 72.7% of men with SSc followed at our department. There was a statistically significant association between ErS and male gender (p.

New hetero-arylidene-9(10H)-anthrone derivatives (1) were synthesized from reaction of 1,2-dimethyl-3-alkyl imidazolium salts (2) and 9-anthracenecarboxaldehyde. Ion exchange of the anion with dioctyl sulfosuccinate and lithium bis(trifluoromethanesulfonyl)imide led to the preparation of other derivatives. The antiproliferative effect of the compounds was evaluated in human ovarian (A2780) and colorectal (HCT116) carcinoma cell lines and in normal primary human fibroblasts. Compound 1 presented an antiproliferative effect related to the imidazolium pattern of substitution with compounds having a decyl group at the R-position (1c and 3c) showing the highest cytotoxic activities in all cell lines independently of the counter ion. Compounds 1b and 1c internalize A2780 cancer cells via a passive or an active transport, respectively, inducing A2780 cell death via an extrinsic apoptosis (1b) or intrinsic apoptosis and oncosis (1c). The localization of both compounds in the cytoplasm coupled to the absence of reactive oxygen species (ROS) induction suggest that the mechanisms of toxicity might be different than those of other anthracyclines currently used in chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The vasculitides are a group of rare diseases with different manifestations and outcomes. New therapeutic options have led to the need for long-term registries. The Rheumatic Diseases Portuguese Register, Reuma.pt, is a web-based electronic clinical record, created in 2008, which currently includes specific modules for 12 diseases and > 20,000 patients registered from 79 rheumatology centres. On October 2014, a dedicated module for vasculitis was created as part of the European Vasculitis Society collaborative network, enabling prospective collection and central storage of encrypted data from patients with this condition. All Portuguese rheumatology centres were invited to participate. Data regarding demographics, diagnosis, classification criteria, assessment tools, and treatment were collected. We aim to describe the structure of Reuma.pt/vasculitis and characterize the patients registered since its development., Results: A total of 687 patients, with 1945 visits, from 13 centres were registered; mean age was 53.4 ± 19.3 years at last visit and 68.7% were females. The most common diagnoses were Behçet's disease (BD) (42.5%) and giant cell arteritis (GCA) (17.8%). Patients with BD met the International Study Group criteria and the International Criteria for BD in 85.3 and 97.2% of cases, respectively. Within the most common small- and medium-vessel vasculitides registered, median [interquartile range] Birmingham Vasculitis Activity Score (BVAS) at first visit was highest in patients with ANCA-associated vasculitis (AAV) (17.0 [12.0]); there were no differences in the proportion of patients with AAV or polyarteritis nodosa who relapsed (BVAS≥1) or had a major relapse (≥1 major BVAS item) during prospective assessment (p = 1.00, p = 0.479). Biologic treatment was prescribed in 0.8% of patients with GCA, 26.7% of patients with AAV, and 7.6% of patients with BD. There were 34 (4.9%) deaths reported., Conclusions: Reuma.pt/vasculitis is a bespoke web-based registry adapted for routine care of patients with this form of rare and complex diseases, allowing an efficient data-repository at a national level with the potential to link with other international databases. It facilitates research, trials recruitment, service planning and benchmarking.

Objectives: After consultations, the physician's perceptions differ from the patient's perceptions concerning illness level, cause, and nature of the problem and content of the consultation. Agreement on problems requiring follow-up was associated with a better outcome. The primary aim of this study was to build and validate an instrument that could assess physician-patient agreement in the rheumatology consultation. The secondary objective was to assess agreement association with patient's clinical and sociodemographic data., Materials and Methods: A ten-item questionnaire - "Consultation Assessment Instrument" (CAI) - was developed for this study to assess the physician-patient agreement. Ten physicians and 102 patients diagnosed with an inflammatory joint disease under biological therapy were included. The items were evaluated and the index of proportional agreement for the dichotomized answers "agree" (Ppos) and "disagree" (Pneg) was calculated., Results: Consultation satisfaction was the item with the highest agreement. On the opposite end, the item about the explanation of treatment importance was the item with the lowest agreement between patient and physician. Except for one item, the high level of agreement between patient and physician was due to a higher Ppos. Index of proportional agreement was high for 9 of the 10 items (0.816≤ Iv ≤0.990). Patients with lower disease activity scores had a more positive experience. A good internal consistency was obtained for both patient's and physician's questionnaire (α = 0.88 and α = 0.80, respectively)., Conclusions: Both patient and physician showed a positive experience towards Rheumatology consultation. Physician-patient agreement was high in the majority of the consultation aspects (mean Iv = 0,93). A good internal consistency was obtained for both patient's and physician's questionnaire. CAI could be useful as a mental checklist in daily practice or as an educational tool for training consultation skills.

Introduction: Shoulder pain is a common cause of consultation in Primary Health Care, and may correspond to up to 30% of the reasons for consultation. Pathology of the rotator cuff is the most common cause of pain. Ultrasound is a valuable diagnostic tool in assessing shoulder disorders; it can be as effective as magnetic resonance imaging., Objective: To determine the predictive factors of response to treatment and ultrasound findings in shoulder pain., Methods: We performed an analysis of the patients' cases sent to the rheumatology consultation with shoulder pain, every patient had an echography shoulder evaluation, and the rheumatologist decided treatment based on the guidelines for the treatment of shoulder tendinopathies. The use of nonsteroidal anti-inflammatory drug (NSAIDs) and muscle relaxant medications as well as the following techniques: corticosteroids local injection, barbotage, capsular distension and physiotherapy programs were some of the variables assessed. Posteriorly, the patients were clinically assessed in a follow-up visit., Results: A total of 119 patients were evaluated. There was a statistically significant relationship between the time from the beginning of the symptomatology and treatment response. Diabetes mellitus, arterial hypertension and dyslipidaemia were statistically significantly associated with some rotator cuff lesions and distention of the subscapular bursa. Age is the main predictor of rotator cuff ultrasound findings., Conclusion: In patients with shoulder pain, early intervention positively influences the response to treatment. Thus, it is important that these patients are evaluated more promptly. Some comorbidities seem to be associated with a higher risk of specific rotator cuff lesions. No relationship was found between response to treatment and age, sex, occupation, previous treatments or type of therapy selected. The associations found in this study seem to have clinical implications. Prevention of rotator cuff disease is a matter of major relevance as well as early institution of treatment.

Objectives: Evaluation and characterization of hand function in patients with rheumatoid (RA) arthritis and, secondarily, identification of the use of adaptive equipments., Material and Methods: Firstly, a written informed consent was obtained and then an anonymous questionnaire was filled by RA outpatients after observation at the rheumatology consultation with no other musculoskeletal or neuromuscular disorders that would determine major functional impairment of hand function. Sociodemographic and clinical variables were collected and the Cochin Hand Functional Scale (CHFS) was applied. Classical deformities of hand and/or wrist were observed and recorded by the attending physician., Results: A total of 79 patients were enrolled. In the overall sample, most patients were female A sample of 79 patients, mostly female (69.60%), with a mean age of 59.72 ± 11.77 years and with a mean diagnosis duration of 11.72 ± 8.29 years. The majority (73.40%) had at least one hand or wrist deformity, the most frequent being atrophy of the interosseous muscles followed by ulnar deviation of the metacarpophalangeal joints and piano key deformity of the wrist. The mean CHFS score was 17.94 ± 18.26 points with a minimum and maximum value recorded of 0 and 80 points, respectively. The presence of hand deformities, Health Assessment Questionnaire score (HAQ), hand pain and diagnosis duration were correlated with the CHFS score. Six patients had assistive devices and only in one case it was used to overcome hand's functional impairment., Conclusions: Most patients presented at least one classic RA deformity after a mean diagnosis duration of approximately 12 years and under pharmacological treatment. Despite this, most patients scored significantly below CHFS maximum score, but only 18 reported no difficulty in any of the tasks mentioned in the scale. The fact that only a minority of these patients had assistive devices should alerts us to the need for a more thorough functional assessment and identification of needs among RA patients.

For the first time, 1,2-dimethyl-3-ethylimidazolium iodide (1a) catalyzes the ring opening of the bicyclic amidine system of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicyclo[4.3.0]non-5-ene) on reaction with aldehydes. The mechanism here proposed involves an N-heterocyclic olefin (NHO) catalytic species that acts as a nucleophile to promote the cyclic amidine ring opening. The resulting ε-caprolactam- and γ-lactam-derived imines were obtained in moderate to excellent yields (28-99%) and reduced to the corresponding amines by sodium borohydride. Confirmation of the imine product was achieved via single-crystal X-ray diffraction studies.

The study was conducted in order to investigate adherence in patients with Rheumatoid arthritis (RA), correlating it with other variables such as affect and self-esteem. Seventy-eight patients with RA between 20 and 81 years of age were evaluated. Patients were assessed for Medical Outcomes Study (MOS) Measures of Patient Adherence, Rosenberg self-esteem scale and Short Portuguese version of the Positive and Negative Affect Schedule (PANAS). Pearson's correlation coefficient was used to assess the correlation between the therapeutic compliance and age, disease activity, disability, GPA, self-esteem, affect and inflammatory parameters. An independent T-test was used to evaluate differences in adherence within gender. The one-way analysis of variance (ANOVA) was used to determine associations between adherence and marital status, education level and employment status. A linear regression model was adjusted with stepwise data entry to determine predictors of therapeutic compliance. Patients had a mean age of 57 years and disease duration of 12.8 years. We observed higher levels of adherence in patients with higher self-esteem (r= 0.343, p&lt0.05) and positive affect (r= 0.345, p&lt0.01). The adjusted linear regression model allowed the identification of positive affect as a RA patient's adherence predictor (R = 0.347, p&lt0.05). In our study, high levels of self-reported adherence in RA patients were found. Positive affect seems to be an important determinant of therapeutic adherence in RA patients. These results suggest a relevant role of psychosocial aspects in therapeutic compliance and outcome, which should alert physicians to the need of an holistic approach of the patient.

Objectives: To compare the effectiveness of a 2nd TNF inhibitor (TNFi), Tocilizumab (TCZ) and Rituximab (RTX), measured by drug retention and by response rates, in RA patients after discontinuing a first-line TNFi and to clarify the reasons and predictors for discontinuation of a second-line biologic., Material and Methods: Non-interventional prospective study of RA patients exposed to a 2nd TNFi, TCZ or RTX after previous TNFi discontinuation using real-world data from Reuma.pt database. Drug retention was estimated using Kaplan-Meier analysis and Cox models. Crude and LUNDEX adjusted response rates were evaluated at 6 months, 1 and 2 years and reasons for discontinuation were compared according to biologic class., Results: In total, 643 patients were included, 88.8% females, with a mean age of 59.4±12.8 years. Of those, 390 (60.7%) initiated a 2nd TNFi, 147 (22.9%) TCZ and 106 (16.5%) RTX. Drug retention was significantly greater among patients who initiated TCZ (76.4±4.3 months) or RTX (80.8±4.8 months), compared with those who initiated a 2nd TNFi (52.7±2.6 months) (log rank test, p < 0.001). In the adjusted Cox model, hazards of discontinuation were significantly lower for TCZ (HR 0.39, 95% CI 0.23-0.64, p < 0.001) and RTX (HR 0.42, 95% CI 0.25-0.72, p=0.001). Smokers had a significantly higher risk for discontinuation (HR 2.43, 95%CI 1.50-3.95, p < 0.001) as well as patients with higher HAQ at baseline (HR 1.51, 95%CI 1.14-2.00, p=0.004). The proportion of patients in remission or low disease activity according to Clinical Disease Activity Index (CDAI) at 6 months, 1 and 2 years was, respectively, 46.5%/50.0%/61.2% for TNFi, 52.9%/53.6%/ 69.2% for TCZ and 37.7%/48.0%/50.0% for RTX. After LUNDEX adjustment, response rates were, respectively, 33.0%/31.0%/31.8% for 2nd TNFi, 42.8%/41.8%/53.3% for TCZ and 32.0%/39.4%/39.0% for RTX. The main reasons for discontinuation were inefficacy for 2nd TNFi and RTX and adverse events for TCZ (p < 0.001)., Conclusions: Our findings showed a significantly higher drug retention for TCZ and RTX, compared with 2nd TNFi, and similar persistence among TCZ and RTX, in patients who discontinued a first-line TNFi. These data corroborate the notion that switching to a biologic with a different mode of action is more effective than to a second TNFi.

(R)-Metacycloprodigiosin can exist in three different tautomeric forms, each with hydrogens at C9' and C12 in syn or anti orientation. With the addition of HCl, this structural diversity reduces to syn-(R)-metacycloprodigiosin-HCl (1a) and anti-(R)-metacycloprodigiosin-HCl (1b), each with multiple conformers. Energetics and chiroptical properties, namely, electronic circular dichroism (ECD) and specific optical rotation (SOR), of (R)-metacycloprodigiosin-HCl have been investigated at B3LYP/6-311++G(2d,2p) level. The experimental ECD spectra of (R)-metacycloprodigiosin-HCl have also been measured. Calculations indicated that the lowest energy conformer of 1b is approximately 2.7 kcal/mol lower in energy than that of 1a, and the energy barrier for anti to syn conversion is approximately 13 kcal/mol. The population weighted calculated SORs of 1a and 1b are, respectively, positive and negative. The respective calculated ECD spectra of these pseudoenantiomers show an almost mirror image relationship between them. The experimental SOR and ECD compare well with those predicted for 1b. Thus, 1b is expected to be predominant, a situation confirmed also by nuclear Overhauser effect (NOE) data, with a similar conclusion reached for prodigiosin R1., (© 2018 Wiley Periodicals, Inc.)

Systemic sclerosis is a connective tissue disease characterized by a complex pathogenesis and a multi organ involvement of unknown etiology. Genetic features and environmental factors, as the use of some drugs, influence the onset of the clinical picture. The authors describe a case of a patient who developed systemic sclerosis after treatment of melanoma with interferon alfa-2b, drug rarely implicated in the induction of this disease.

Aim: To identify if the use of a systematic ultrasound (US) evaluation has relevance in the determination of disease activity in rheumatoid arthritis patients on biological disease-modifying anti-rheumatic drug treatment., Methods: A 12 joint US assessment was performed on the same day of the routine clinical examination. Both Grey-scale (GS) and Power Doppler (PD) were graded semi-quantitatively (0-3 scale)., Results: Forty-one patients were included. GS or PD > 0 were found in 24% and 3% of the ankles, 21% and 17% of the wrists, 19% and 9% of the second metacarpophalangeal joints (MCP), 7% and 2% of the third MCP, 6% and 0% of the knees and 5% and 0% of the elbows, respectively; tenosynovitis of the tibialis posterior was found in 19% of the ankles. Eight of the patients with Disease Activity Score of 28 joints (DAS28) ≤ 2.6 (n = 15) had an US score of 0. Twenty-seven joints (6.7%) had US evidence of synovitis but were not considered to be swollen; 10 (2.5%) were considered to be swollen but had no US evidence of synovitis., Conclusions: Using a 12 joint US assessment, a high proportion of patients with DAS28 < 2.6 were found to have inflammatory US activity, and a significant proportion of patients had evidence of tenosynovitis of the tibialis posterior, which may be difficult to clinically detect. A regular and standardized US assessment of RA patients is therefore warranted to complement clinical evaluation and better define disease activity., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Unexpected and unusual reactivity of 2-methylimidazolium salts toward aryl-N-sulfonylimines and aryl aldehydes is here reported. Upon reaction with aryl-N-sulfonylimines, the addition product, arylethyl-2-imidazolium-1-tosylamide (3), is formed with moderate to good yields, while upon reaction with aldehydes, the initial addition product (6) observed in NMR and HPLC-MS experimental analysis is postulated by us as an intermediate to the final conversion to carboxylic acids. Studies in the presence and absence of molecular oxygen allow us to conclude that the imidazolium salts is crucial for the oxidation. A detailed mechanistic study was carried out to provide insights regarding this unexpected reactivity.

The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC₅₀ values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC₅₀ 10-28 nM) bearing hydrophobic groups (Me, F, CF₃ and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 μM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

New fluorinated and methoxylated di(hetero)arylethers and di(hetero)arylamines were prepared functionalizing the 7-position of the thieno[3,2-b]pyridine, using copper (C-O) or palladium (C-N) catalyzed couplings, respectively, of the 7-bromothieno[3,2-b]pyridine, also prepared, with ortho, meta and para fluoro or methoxy phenols and anilines. The compounds obtained were evaluated for their growth inhibitory activity on the human tumor cell lines MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), HCT15 (colon carcinoma), HepG2 (hepatocellular carcinoma) and HeLa (cervical carcinoma). The most active compounds, a di(hetero)arylether with a methoxy group in the meta position relative to the ether function and two di(hetero)arylamines with a methoxy group either in the ortho or in the meta position relative to the NH, were further tested at their GI50 concentrations on NCI-H460 cells causing pronounced alterations in the cell cycle profile and a strong and significant increase in the programmed death of these cells. The fluorinated and the other methoxylated compounds did not show important activity, presenting high GI₅₀ values in all the cell lines tested. Furthermore, the hepatotoxicity of the compounds was assessed using porcine liver primary cells (PLP2), established by some of us. Results showed that one of the most active compounds was not toxic to the non-tumor cells at their GI₅₀ concentrations showing to be the most promising as antitumoral., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objectives: To develop Portuguese evidence-based recommendations for pain management by pharmocotherapy in inflammatory arthritis., Methods: The Portuguese project was integrated in the multinational 3E Initiative (Evidence, Expertise, Exchange) 2010 where a total of 453 rheumatologists from 17 countries have participated. The clinical questions concerning pain were formulated and the Portuguese group added 2 more questions. A systematic literature search was performed in Medline, Embase, Cochrane Library and 2008-2009 EULAR and ACR abstracts. The selected articles were systematically reviewed and the evidence was defined according to the Oxford Levels of Evidence. In each country a group of experts joined to discuss their national recommendations. In Portugal, the national meeting was held in October 2010, where 33 rheumatologists discussed and voted by Delphi method the national recommendations. Finally, the agreement among the rheumatologists and the potential impact on their clinical practice was assessed., Results: Thirteen national recommendations were formulated: pain measure scores; analgesic combination therapy; pharmacotherapy in preconception, pregnancy and lactation periods; pharmacotherapy according to comorbilities; safety of NSAIDs and/or paracetamol with methotrexate combination therapy; efficacy and safety of continuous/on-demand NSAIDs; opioids, paracetamol, corticosteroids, antidepressants, neuromodulators and muscle relaxants role and effectiveness; risk factors for the development of chronic pain and the role of topic analgesics., Conclusion: The portuguese recommendations for the pain management by pharmacotherapy in inflammatory arthritis were formulated according to the best evidence and supported by a panel of 63 rheumatologists. The differences between the national and international recommendations are reported in this article.