Objective: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with antitumour necrosis factor (TNF) agents. Methods: UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). Results: Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. Conclusion: The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22.

Bladder cancer (BCA) is relatively common and potentially recurrent/progressive disease. It is also costly to detect, treat, and control. Definitive diagnosis is made by examination of urine sediment, imaging, direct visualization (cystoscopy), and invasive biopsy of suspect bladder lesions. There are currently no widely-used BCA-specific biomarker urine screening tests for early BCA or for following patients during/after therapy. Urine metabolomic screening for biomarkers is costly and generally unavailable for clinical use. In response, we developed Raman spectroscopy-based chemometric urinalysis (Rametrix™) as a direct liquid urine screening method for detecting complex molecular signatures in urine associated with BCA and other genitourinary tract pathologies. In particular, the Rametrix TM screen used principal components (PCs) of urine Raman spectra to build discriminant analysis models that indicate the presence/absence of disease. The number of PCs included was varied, and all models were cross-validated by leave-one-out analysis. In Study 1 reported here, we tested the Rametrix™ screen using urine specimens from 56 consented patients from a urology clinic. This proof-of-concept study contained 17 urine specimens with active BCA (BCA-positive), 32 urine specimens from patients with other genitourinary tract pathologies, seven specimens from healthy patients, and the urinalysis control Surine TM. Using a model built with 22 PCs, BCA was detected with 80.4% accuracy, 82.4% sensitivity, 79.5% specificity, 63.6% positive predictive value (PPV), and 91.2% negative predictive value (NPV). Based on the number of PCs included, we found the Rametrix TM screen could be fine-tuned for either high sensitivity or specificity. In other studies reported here, Rametrix TM was also able to differentiate between urine specimens from patients with BCA and other genitourinary pathologies and those obtained from patients with end-stage kidney disease (ESKD). While larger studies are needed to improve Rametrix TM models and demonstrate clinical relevance, this study demonstrates the ability of the Rametrix TM screen to differentiate urine of

Objective. To test the intra-and interobserver variability, among clinicians with an interest in systemic sclerosis (SSc), in defining digital ulcers.Methods. Thirty-five images of finger lesions, incorporating a wide range of abnormalities at different sites, were duplicated, yielding a data set of 70 images. Physicians with an interest in SSc were invited to take part in the Web-based study, which involved looking through the images in a random sequence. The sequence differed for individual participants and prevented crosschecking with previous images. Participants were asked to grade each image as depicting "ulcer" or "no ulcer," and if "ulcer," then either "inactive" or "active." Images of a range of exemplar lesions were available for reference purposes while participants viewed the test images. Intrarater reliability was assessed using a weighted kappa coefficient with quadratic weights. Interrater reliability was estimated using a multirater weighted kappa coefficient.Results. Conclusion.The poor interrater reliability suggests that if digital ulceration is to be used as an end point in multicenter clinical trials of SSc, then strict definitions must be developed. The present investigation also demonstrates the feasibility of Web-based studies, for which large numbers of participants can be recruited over a short time frame.Digital ulcers, which are common in patients with systemic sclerosis (SSc) (1,2), are painful and disabling. These types of ulcers are often used as a primary end point in clinical trials of SSc-related digital ischemia and vasculopathy, as was the case in 2 recent multicenter placebo-controlled trials (3,4). Patient-assessed digital ulcer "activity" was among a core set of measures proposed for use in trials of SSc-related Raynaud's phenomenon (5). However, digital ulcers are difficult to define, which raises concerns about their reliability as an outcome measure. Problems include 1) making the distinction between "healed" and "nonhealed" ulcers, which can be difficult with lesions situated on the fingertips and the extensor surfaces, since an ulcer crater can persist for months after an acute episode, and 2) determining which sites to use. The study by Korn et al (3) included only those ulcers at or distal to the proximal interphalangeal joints, and yet, more proximal ulcers (e.g., those over the metacarpophalangeal joints) can be very painful, and healing can be difficult.

Our results suggest that dermoscopy is comparable to NVC, although NVC images were more likely to be classifiable and were graded more severely.

ObjectiveDigital ulcers (DUs) are often a primary end point in systemic sclerosis (SSc; scleroderma) clinical trials, although the reliability of rheumatologists grading DUs is poor to moderate at best. DU assessment in recent trials has been based upon visual inspection alone, which potentially misses “real‐world” clinical contextual information. Our aim was to investigate whether this clinical information improves the reliability of rheumatologists grading DUs. A secondary aim was to assess agreement between patients and rheumatologists.MethodsEighty images of a range of digital lesions were collected from patients with SSc with the clinical context: pain (severity and temporal relationship), lesion duration, and discharge (patient reported and clinician observed). Raters received all images either with or without the clinical context, and graded these images (using a custom‐built interface) on an ordinal scale of severity: no ulcer, inactive ulcer, or active ulcer. Patients also graded their lesion(s) on the same scale.ResultsFifty‐one rheumatologists from 15 countries completed the study (26 without and 25 with context): 4,590 (including 510 repeated) image gradings were obtained. Context did not significantly increase (without and with context) either intra‐ (0.64, 0.71) or interrater (0.32, 0.36) reliability. Pain (visual analog scale and temporal relationship) and discharge (patient reported and clinician observed) were associated with increased lesion severity, and duration with reduced severity. Agreement between individual patients and rheumatologists was poor without and with context (0.19, 0.28).ConclusionThe overall intra‐ and interrater reliability of DU grading did not significantly improve with the clinical context. Agreement between patients and rheumatologists was poor.

Perfusate flow is dependent on bladder perfusion pressure, and not necessarily reciprocally dependent on vesical pressure. Vesical pressure is highly sensitive to the level of perfusate flow, which supports the hypothesis that vesical pressure is dependent on the level of detrusor smooth muscle contractile activity (tone), and that compliance is dependent on bladder perfusion.

No abstract

Although our proposed digital ulcer definitions had high intra-rater reliability, the overall inter-rater reliability was poor. Our study highlights the challenges of digital ulcer assessment by clinicians with an interest in systemic sclerosis and provides a number of useful insights for future clinical trial design. Further research is warranted to improve the reliability of digital ulcer definition/rating as an outcome measure in clinical trials, including examining the role for objective measurement techniques, and the development of digital ulcer patient-reported outcome measures.