A Practical Approach to the Use of Conventional Synthetic, Biologic and Targeted Synthetic Disease Modifying Anti-Rheumatic Drugs for the Treatment of Inflammatory Arthritis in Patients with a History of Malignancy.

PURPOSE OF REVIEW: Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) have been used in the treatment of inflammatory arthritis (IA) for many years. More recently, biologic (bDMARDs) and targeted synthetic (tsDMARDs) DMARDs have further improved treatment. Due to increased patient longevity and effective oncology treatment, rheumatologists often encounter patients with IA and previous malignancy. The immunosuppressive effect of DMARDs causes concern regarding impaired tumour surveillance with a potential increased risk of malignancy. We reviewed the literature regarding the risk of malignancy in patients on cs-/b-/tsDMARDS and sought to provide practical advice regarding use of these drugs in patients with previous malignancy. RECENT FINDINGS: Data from randomised controlled trials is limited as patients with pre-existing malignancy are often excluded. Reassuringly, an increasing range of "real world" data from various national b/tsDMARD registries has not provided a convincing signal that these drugs increase tumour recurrence. Nevertheless, awareness of, and adherence to, national screening guidelines for malignancy is important. Given the improvement in quality of life achieved with these novel and well-tolerated therapeutic agents, the benefit/risk profile remains overwhelmingly favourable in most patients.

EVOLVE: The Australian Rheumatology Association's 'top five' list of investigations and interventions doctors and patients should question.

BACKGROUND: The EVOLVE (evaluating evidence, enhancing efficiencies) initiative aims to drive safer, higher-quality patient care through identifying and reducing low-value practices. AIMS: To determine the Australian Rheumatology Association's (ARA) 'top five' list of low-value practices. METHODS: A working group comprising 19 rheumatologists and three trainees compiled a preliminary list. Items were retained if there was strong evidence of low value and there was high or increasing clinical use and/or increasing cost. All ARA members (356 rheumatologists and 72 trainees) were invited to indicate their 'top five' list from a list of 12-items through SurveyMonkey in December 2015 (reminder February 2016). RESULTS: A total of 179 rheumatologists (50.3%) and 19 trainees (26.4%) responded. The top five list (percentage of rheumatologists, including item in their top five list) was: Do not perform arthroscopy with lavage and/or debridement for symptomatic osteoarthritis of the knee nor partial meniscectomy for a degenerate meniscal tear (73.2%); Do not order anti-nuclear antibody (ANA) testing without symptoms and/or signs suggestive of a systemic rheumatic disease (56.4%); Do not undertake imaging for low back pain for patients without indications of an underlying serious condition (50.8%); Do not use ultrasound guidance to perform injections into the subacromial space as it provides no additional benefit in comparison to landmark-guided injection (50.3%) and Do not order anti-double-stranded DNA antibodies in ANA negative patients unless the clinical suspicion of systemic lupus erythematosus remains high (45.3%). CONCLUSIONS: This list is intended to increase awareness among rheumatologists, other clinicians and patients about commonly used low-value practices that should be questioned.

Substituted azaquinazolinones as modulators of GHSr-1a for the treatment of type II diabetes and obesity.

Substituted azaquinazolinones were identified as antagonists of the GHSr-1A receptor for the treatment of type II diabetes and obesity. Optimisation for potency and LogD lead to the identification of orally bioavailable, potent antagonists with improved selectivity over hERG.

Management of vaccination in rheumatic disease.

Autoimmune inflammatory rheumatic diseases (AIIRD) such as rheumatoid arthritis and spondyloarthritis, including psoriatic arthritis and ankylosing spondylitis are associated with an increased risk of infection due to a combination of the immunosuppressive effect of the AIIRD, comorbidities, and use of corticosteroids and the immunosuppressive effect of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts-) DMARDs, and biologic (b-) DMARDs. Many infections are preventable with vaccination. However, as the protective immune responses induced by vaccination may be impaired by immunosuppression, vaccination should be considered before the commencement of immunosuppression. Another opportune time to review vaccination status is when planning overseas travel, as destination-specific vaccines are often required. Although limited published data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult, a vaccination history should be part of the initial workup in all patients with AIIRD. Unfortunately, this is often not done by rheumatologists. This paper encourages those caring for patients with AIIRD to regularly review vaccination status.

Muscle involvement in mixed connective tissue disease.

Muscle disease has been recognized as a common feature of mixed connective tissue disease (MCTD) since its first description in 1972. In the absence of clinical trials that are directed specifically at the myositis of MCTD, patients should be treated in the manner that is recommended for other forms of myositis. Myositis of MCTD may have a better prognosis than other forms of myositis.

Preparation and stereochemical integrity of certain thioesters of 2-arylpropionic acids and related compounds.

2-Arylpropionate thioesters 5, 6a/6b and 7a/7b, 2-aryloxypropionate thioesters 8a/8b and 2-alkoxy-2-arylacetate thioesters 9a/9b were prepared from thiol 4 and the corresponding carboxylic acids. Thioesters 6a/6b, 7a/7b, 8a/8b and 9a/9b were monitored for evidence of inter-conversion between epimers in acetonitrile solvent at 40 degrees C, by optical activity in the cases of 6a/6b and 7a/7b, and by 1H NMR spectroscopy in the cases of 8a/8b and 9a/9b. Only in the case of thioesters 9a/9b was significant inter-conversion between epimers observed.

Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study.

PURPOSE: To evaluate the efficacy and upper gastrointestinal (UGI) safety of celecoxib, compared with nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), among patients with osteoarthritis. METHODS: A total of 13274 osteoarthritis patients from 39 countries were randomly assigned to double-blind treatment with either celecoxib 100 mg twice daily (BID), celecoxib 200 mg BID, or nonselective NSAID therapy (diclofenac 50 mg BID or naproxen 500 mg BID) for 12 weeks. Standard validated measures were used to assess osteoarthritis efficacy. Serious UGI events were evaluated by 2 blinded, independent, gastrointestinal events committees. RESULTS: Results from all primary efficacy assessments showed that both dosages of celecoxib were as effective as NSAIDs in treating osteoarthritis. Significantly more ulcer complications occurred within the nonselective NSAID group (0.8/100 patient-years) compared with the celecoxib group (0.1/100 patient-years) (odds ratio = 7.02; 95% confidence interval [CI], 1.46 to 33.80; P =.008). There were fewer ulcer complications in the celecoxib group compared with the NSAID group, both in patients taking concomitant aspirin and those not taking aspirin, but the difference reached statistical significance only in the latter comparison. The number of cardiovascular thromboembolic events was low and not statistically different between the groups (eg, myocardial infarction rates: celecoxib 10 events [0.55/100 patient-years] vs NSAIDs 1 event [0.11/100 patient-years], (P =.11), but the study was not powered to detect such differences. CONCLUSIONS: In the treatment of osteoarthritis, celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac, but has significantly fewer serious upper gastrointestinal events.

The Plume Volume Molar Ratio Method for Determining NO2/NOx Ratios in Modeling-Part II: Evaluation Studies.

A previous paper1 discusses the methodology for a new method for deriving the nitrogen dioxide/nitrogen oxide (NO2/NOx) ratio in plumes that originally are composed mainly of (NOx). It is called the Plume Volume Molar Ratio Method (PVMRM). This paper documents its performance against six different data sets. These performance evaluations show that the PVMRM can realistically predict the NO2 fraction at close-in receptors yet still provide conservative estimates so that the air quality standards can be protected.

The Plume Volume Molar Ratio Method for Determining NO2/NOx Ratios in Modeling-Part I: Methodology.

During New Source Review modeling of proposed major sources of oxides of nitrogen (NOx), maximum impacts are often predicted to occur very close to the source. At the same time, current modeling guidance recommends techniques that may be overly conservative in estimating the fraction of nitrogen dioxide (NO2) in these plumes. A new technique called the Plume Volume Molar Ratio Method (PVMRM) is being proposed that simulates both chemistry and dispersion to better estimate the fraction of NO2. This paper documents the methodology behind the technique. A follow-up pa-per1 will evaluate its performance against a number of databases. This method is designed to realistically predict NO2 fraction at close-in receptors yet still provide conservative estimates so that the air quality standards can be protected.