Multiplex plasma protein assays as a diagnostic tool for lung cancer.

Lack of the established noninvasive diagnostic biomarkers causes delay in diagnosis of lung cancer (LC). The aim of this study was to explore the association between inflammatory and cancer-associated plasma proteins and LC and thereby discover potential biomarkers. Patients referred for suspected LC and later diagnosed with primary LC, other cancers, or no cancer (NC) were included in this study. Demographic information and plasma samples were collected, and diagnostic information was later retrieved from medical records. Relative quantification of 92 plasma proteins was carried out using the Olink Immuno-Onc-I panel. Association between expression levels of panel of proteins with different diagnoses was assessed using generalized linear model (GLM) with the binomial family and a logit-link function, considering confounder effects of age, gender, smoking, and pulmonary diseases. The analysis showed that the combination of five plasma proteins (CD83, GZMA, GZMB, CD8A, and MMP12) has higher diagnostic performance for primary LC in both early and advanced stages compared with NC. This panel demonstrated lower diagnostic performance for other cancer types. Moreover, inclusion of four proteins (GAL9, PDCD1, CD4, and HO1) to the aforementioned panel significantly increased the diagnostic performance for primary LC in advanced stage as well as for other cancers. Consequently, the collective expression profiles of select plasma proteins, especially when analyzed in conjunction, might have the potential to distinguish individuals with LC from NC. This suggests their utility as predictive biomarkers for identification of LC patients. The synergistic application of these proteins as biomarkers could pave the way for the development of diagnostic tools for early-stage LC detection.

Distinct Fluorescence Optical Imaging Patient Clusters Emerge for Seropositive and Seronegative Rheumatoid Arthritis.

OBJECTIVE: To investigate whether digital activity fluorescence optical imaging (FOI) patterns of inflammation can identify distinct rheumatoid arthritis (RA) phenotypes. METHODS: The hands of newly diagnosed patients with RA were evaluated by clinical examination, musculoskeletal ultrasound, and FOI. Inflammation on FOI was defined when capillary leakage and/or fluorophore perfusion was present. The FOI composite image was quantified into a digital disease activity (DACT) score, using novel computerized algorithms. Unsupervised clustering on FOI inflammatory patterns was used to identify subgroups of patients relative to anticyclic citrullinated peptides (ACPA) and/or rheumatoid factor (RF). RESULTS: Of 1326 examined hand joints in 39 patients with RA (72% female; 56% ever-smokers; 54% RF positive and 69% ACPA positive), 400 (30%) showed inflammation by FOI, and 95% (37 of 39) of patients had DACT-FOI scores greater than 1. Unsupervised analysis on FOI patterns revealed two patient clusters, cluster 1 (n = 29) and cluster 2 (n = 10). The proportion of seropositive patients was significantly higher in cluster 1 versus cluster 2 (90%, 26 of 29 vs. 30%, 3 of 10; P < 0.01), whereas C-reactive-protein levels (minimum-maximum) were significantly higher in cluster 2 (20 mg/l [1-102]) versus cluster 1 (2 mg/l [0-119]; P = 0.01). A wider variety and proportion of inflamed joints emerged for patients with RA in cluster 2 versus cluster 1, in which inflammation was more concentrated around the wrists and the right metacarpophalangeal 2 (MCP2), bilateral MCP3, and, to a lesser degree, left MCP2 and proximal interphalangeal joint and tendon regions. Cluster 1 displayed lower mean (±SD) DACT scores compared with cluster 2 (3.6 ± 2.1 vs. 5.4 ± 2.1; P = 0.03). CONCLUSION: FOI-based digital quantification of hand joint inflammation revealed two distinct RA subpopulations with and without ACPA and RF related autoantibodies.

Using patients' own knowledge of early sensations and symptoms to develop an interactive, individualized e-questionnaire to facilitate early diagnosis of lung cancer.

BACKGROUND: One reason for the often late diagnosis of lung cancer (LC) may be that potentially-indicative sensations and symptoms are often diffuse, and may not be considered serious or urgent, making their interpretation complicated. However, with only a few exceptions, efforts to use people's own in-depth knowledge about prodromal bodily experiences has been a missing link in efforts to facilitate early LC diagnosis. In this study, we describe and discuss facilitators and challenges in our process of developing and initial testing an interactive, self-completion e-questionnaire based on patient descriptions of experienced prodromal sensations and symptoms, to support early identification of lung cancer (LC). METHODS: E-questionnaire items were derived from in-depth, detailed explorative interviews with individuals undergoing investigation for suspected LC. The descriptors of sensations/symptoms and the background items obtained were the basis for developing an interactive, individualized instrument, PEX-LC, which was refined for usability through think-aloud and other interviews with patients, members of the public, and clinical staff. RESULTS: Major challenges in the process of developing PEX-LC related to collaboration among many actors, and design/user interface problems including technical issues. Most problems identified through the think-aloud interviews related to design/user interface problems and technical issues rather than content, for example we re-ordered questions to be in line with patients' chronological, rather than retrospective, descriptions of their experiences. PEX-LC was developed into a final e-questionnaire on a touch-screen smart tablet with one background module covering sociodemographic characteristics, 10 interactive, individualized modules covering early sensations and symptoms, and a 12th assessing current symptoms. CONCLUSIONS: Close collaboration with patients throughout the process was intrinsic for developing PEX-LC. Similarly, we recognized the extent to which clinicians and technical experts were also important in this process. Similar endeavors should assure all necessary competence is included in the core research team, to facilitate timely progress. Our experiences developing PEX-LC combined with new empirical research suggest that this individualized, interactive e-questionnaire, developed through systematizing patients' own formulations of their prodromal symptom experiences, is both feasible for use and has potential value in the intended group.

Early symptoms and sensations as predictors of lung cancer: a machine learning multivariate model.

The aim of this study was to identify a combination of early predictive symptoms/sensations attributable to primary lung cancer (LC). An interactive e-questionnaire comprised of pre-diagnostic descriptors of first symptoms/sensations was administered to patients referred for suspected LC. Respondents were included in the present analysis only if they later received a primary LC diagnosis or had no cancer; and inclusion of each descriptor required ≥4 observations. Fully-completed data from 506/670 individuals later diagnosed with primary LC (n = 311) or no cancer (n = 195) were modelled with orthogonal projections to latent structures (OPLS). After analysing 145/285 descriptors, meeting inclusion criteria, through randomised seven-fold cross-validation (six-fold training set: n = 433; test set: n = 73), 63 provided best LC prediction. The most-significant LC-positive descriptors included a cough that varied over the day, back pain/aches/discomfort, early satiety, appetite loss, and having less strength. Upon combining the descriptors with the background variables current smoking, a cold/flu or pneumonia within the past two years, female sex, older age, a history of COPD (positive LC-association); antibiotics within the past two years, and a history of pneumonia (negative LC-association); the resulting 70-variable model had accurate cross-validated test set performance: area under the ROC curve = 0.767 (descriptors only: 0.736/background predictors only: 0.652), sensitivity = 84.8% (73.9/76.1%, respectively), specificity = 55.6% (66.7/51.9%, respectively). In conclusion, accurate prediction of LC was found through 63 early symptoms/sensations and seven background factors. Further research and precision in this model may lead to a tool for referral and LC diagnostic decision-making.

Joint Mobilization of the Hands of Patients With Rheumatoid Arthritis: Results From an Assessor-Blinded, Randomized Crossover Trial.

OBJECTIVE: The purpose of this study was to assess the clinical feasibility and effectiveness of manual mobilization of the hands of patients with rheumatoid arthritis (RA). METHODS: A total of 320 individual hand joints were evaluated after recruiting an experimental research group of 12 participants with RA and, for clinical comparability, 8 participants with hand osteoarthritis (OA). One hand per participant was randomized to receive weekly low-grade (I-II) Kaltenborn manual mobilization, using passive sustained stretch of the metacarpophalangeal (MCP) joints II to V by licensed manual therapists. After 2 weeks, the randomized treated hand was crossed over to control (untreated) during weeks 3 to 4 and vice versa. Final assessment was at 2 months, which was 1 month after the last treatment at week 4. Primary hand outcomes included pain by visual analog scale, tender or swollen joint count, and presence of Doppler signal or synovial fluid and radiographic joint space by musculoskeletal ultrasound. RESULTS: In the RA group, both the initially randomized treated hand and the contralateral hand improved significantly from baseline to crossover to follow-up at 2 months (pain outcomes and Doppler signal, P < .050; synovial fluid and MCP joint space, P ≤ .001). Hand pain and MCP joint space also improved significantly in OA. There were no dropouts or reported adverse events in either the RA or OA group. CONCLUSION: In this study, manual mobilization of the hands of patients with RA was shown to be feasible, safe, and effective to integrate into specialized healthcare.

Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial.

OBJECTIVES: The aim of this paper was to analyse the impact of obesity, in addition to known predictors, on disease outcome in early rheumatoid arthritis (RA). METHODS: Body mass index (BMI) was available in 260 patients from the Swedish pharmacotherapy trial (SWEFOT). Differences in disease activity (DAS28), functional impairment (HAQ), pain (Visual Analogue Scale, VAS-pain) and radiographic damage were evaluated over 24 months between BMI categories (obese BMI >30, n=43; overweight BMI=25-29.9, n=74; normal BMI <25, n=143) using non-parametric testing. Predictors of European League Against Rheumatism non-remission (DAS28 ≥2.6) at 24 months of follow-up were evaluated using binary univariate and multivariate logistic regression. RESULTS: Obesity at baseline was associated with worse continuous-scale clinical outcomes over 24 months (DAS28, HAQ and VAS-pain at last visit: obese vs normal: p<0.001; obese vs overweight: p<0.05). Furthermore, obese patients compared with non-obese patients had significantly greater odds of non-remission at 24 months (adjusted OR (aOR) 5.2; 95% CI 1.8 to 15.2). Other independent predictors were female sex (aOR 2.6; 95% CI 1.1 to 5.8), current smoking (aOR 2.6; 95% CI 1.1 to 6.3) and HAQ (per-unit increase, aOR 1.9; 95% CI 1.1 to 3.4). The pattern was similar among seropositive and seronegative patients; and in the subgroups of methotrexate responders and patients randomised at 3 months to add-on of sulfasalazine+hydroxychloroquine, although not significant with add-on of infliximab. Obesity had no independent association to radiographic progression. CONCLUSIONS: In this early RA trial reflecting today's standard treatment, obesity, in addition to sex, smoking and functional impairment strongly lowered the chance of attaining good clinical outcomes, including remission, today's treatment goal. This highlights the importance of considering lifestyle modification as one of the cornerstones of RA care. TRIAL REGISTRATION NUMBER: NCT00764725; Post-results. WHO database at the Karolinska University Hospital: CT20080004.

Early treatment intensification induces favourable radiographic outcomes according to predicted versus observed radiographic progression in early rheumatoid arthritis: a subanalysis of the randomised FIN-RACo and NEO-RACo trials.

OBJECTIVES: Predicted versus observed radiographic progression in early rheumatoid arthritis (POPeRA) was applied to demonstrate how various treatment modalities affect and potentially minimise radiographic progression over time. METHODS: The POPeRA method utilises the baseline radiographic score and patient-reported symptom duration to predict radiographic outcomes. It was applied at baseline, 2, and 5 years to patients with eRA from the randomised Finnish RA Combination trial (FIN-RACo) (n=144) and New Finnish RA Combination Therapy (NEO-RACo) (n=90) trials. For FIN-RACo, patients were randomised either to a single DMARD (sulfasalazine, with or without prednisolone) or to combination therapy (methotrexate+sulfasalazine+hydroxychloroquine, i.e. triple therapy, with prednisolone). In NEO-RACo, all patients were assigned intensified combination therapy (including 7.5 mg prednisolone/day) plus a randomised 6-month induction of either placebo or anti-TNF treatment (infliximab). RESULTS: In FIN-RACo, combination versus monotherapy resulted in superior outcomes in the change from predicted progression over 2 and 5 years (mean 35.7% reduction vs. -32.9%, a worsening from predicted, p=0.001; 34.2% vs. -17.8%, p=0.003, respectively). In NEO-RACo, combination+anti-TNF induction led to significantly greater reductions from predicted progression than combination+placebo, both at 2 and 5 years of follow-up (98.5% vs. 83.4%, p=0.005; 92.4% vs. 82.5%, p=0.027, respectively). Importantly, anti-TNF add-on led to superior reductions from predicted among RF-positive patients (2 years: 97.4% vs. 80.4%, p=0.009; 5 years: 90.2% vs. 80.1%, p=0.030), but not among RF-negative patients. CONCLUSIONS: These results confirm that conventional combination therapy in eRA has a long-term radiographic benefit versus monotherapy. Through POPeRA, it was made evident that anti-TNF induction therapy for 6 months further increases the long-term radiographic benefit of combination therapy in RF-positive patients.

Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging.

OBJECTIVES: The correct identification of synovitis is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality based on the use of an intravenous fluorophore, which enables fluorescent imaging of the hands and wrists with increased focal optical signal intensities in areas of high perfusion and/or capillary leakage. The study objective was to determine the diagnostic utility of FOI in detecting apparent and clinically non-apparent active synovitis. METHODS: Bilateral hand and wrist joints (n=872) of 26 patients with inflammatory arthritis assessed by standard clinical examination, musculoskeletal ultrasound (MSUS) and FOI were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening and intra-articular Doppler signals on MSUS, and abnormal focal optical signal intensities on FOI, respectively. Subclinical synovitis was defined as being clinically non-apparent, but positively inflamed on MSUS. RESULTS: Depending on the standard used to define inflammation, FOI ranged from 73-83% sensitive and 83-95% specific for detecting manifest synovitis. For detecting clinically silent synovitis, the sensitivity, specificity and positive and negative predictive values of FOI were 80%, 96%, 77% and 97%, respectively. CONCLUSIONS: The high degree of agreement between MSUS and FOI suggest its use in clinical practice, especially when MSUS is not available, in order to identify synovitis earlier and with greater confidence. FOI may be particularly useful in identifying patients with clinically non-apparent joint inflammation of the hands and/or wrists.

Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial.

BACKGROUND: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis. METHODS: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at 3 months, and at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF). RESULTS: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95% CI 1.12-9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01-3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09-9.10), P = 0.037). DISCUSSION: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients. CONCLUSIONS: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy. TRIAL REGISTRATION: WHO database at the Karolinska University Hospital: CT20080004 ; ClinicalTrials.gov: NCT00764725, registered 1 October 2008.

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force.

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.

Biologics in SLE: towards new approaches.

In recent years the use of biologic therapies in the management of systemic lupus erythematosus (SLE) has increased, and a number of clinical trials have highlighted both the potential and the pitfalls in the development of such agents. Many investigators reported that the off-label use of rituximab seemed promising in patients with refractory disease, but randomised trials with this agent failed. Likewise, the theoretical appeal of the co-stimulation blocker abatacept could not be confirmed in two clinical trials. Various considerations and post hoc analyses nonetheless suggest that these two biologics might have a role in the treatment of SLE. The anti-B-lymphocyte stimulator (anti-Blys) antibody belimumab demonstrated efficacy and safety in two large randomised trials and became the first approved biologic for lupus. Use in clinical practice has increased slowly, in part, due to uncertainty over which patients should be treated with this agent and in what stage of the disease. Finally, several other biologic agents are currently in advanced stages of clinical development for SLE. The overall picture that emerges is one of optimism that advances in SLE therapy will be realised through the targeted use of an increasing number of biologics.