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Objectives The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy. Methods Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization. Results Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs. Conclusions In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself. Trial registration ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530.

Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.

Objective Pain is a significant burden for patients with rheumatoid arthritis (RA) despite advancements in treatment. We undertook this study to examine the independent contribution of pain centralization to the pain experience of patients with active RA. Methods A total of 263 RA patients with active disease underwent quantitative sensory testing (QST), including assessment of extraarticular pressure pain thresholds (PPTs), temporal summation (TS), and conditioned pain modulation (CPM). The pain experience was assessed by a pain intensity numeric rating scale and the Patient-Reported Outcomes Measurement Information System pain interference computerized adaptive test. We examined associations between QST measures and pain intensity and pain interference. Multiple linear regression models were adjusted for demographic and clinical variables, including swollen joint count and C-reactive protein level. Results Patients with the lowest PPTs (most central dysregulation) reported higher pain intensity than patients with the highest PPTs (adjusted mean difference 1.02 [95% confidence interval (95% CI) 0.37, 1.67]). Patients with the highest TS (most central dysregulation) had higher pain intensity than those with the lowest TS (adjusted mean difference 1.19 [95% CI 0.54, 1.84]). CPM was not associated with differences in pain intensity. PPT and TS were not associated with pain interference. Patients with the lowest CPM (most centrally dysregulated) had lower pain interference than patients with the highest CPM (adjusted mean difference -2.35 [95% CI -4.25, -0.44]). Conclusion Pain centralization, manifested by low PPTs and high TS, was associated with more intense pain. Clinicians should consider pain centralization as a contributor to pain intensity, independent of inflammation.

Objective The Patient-Reported Outcomes Measurement Information System (PROMIS) is a calibrated item bank used to assess patient-reported outcomes across multiple domains. The purpose of this study was to describe the performance of selected PROMIS measures in patients with rheumatoid arthritis (RA) with active disease who were initiating a disease-modifying antirheumatic drug (DMARD). Methods Participants in an ongoing prospective observational study completed 8 PROMIS measures before and after DMARD initiation. Linear regression models were performed to identify cross-sectional associations between baseline PROMIS measures and disease activity, measured using the Clinical Disease Activity Index (CDAI). Paired t-tests were performed to evaluate responsiveness after 12 weeks of DMARD treatment. Associations between changes in PROMIS measures and changes in the CDAI score were assessed using linear regression. Results Among the 156 participants who completed the first study visit, the mean ± SD baseline CDAI score was 25.5 ± 14.0. Baseline scores for PROMIS measures of physical health, pain, and sleep were associated with the baseline CDAI score (P ≤ 0.05). Among the 106 participants with 12-week data, all PROMIS scores improved after DMARD initiation (P ≤ 0.05). With the exception of depression, changes in all assessed PROMIS measures were correlated with changes in the CDAI score (standardized βs from |0.23| to |0.38|). Conclusion These data provide support for the utility of PROMIS measures for the assessment of physical and mental health in individuals with active RA. All PROMIS measures improved significantly after DMARD initiation, with the magnitudes of association between changes in PROMIS measures and changes in the CDAI score in the low-to-moderate range.

The authors aimed to evaluate the efficacy of low-dose naltrexone in the management of chronic pain conditions and determine its potential use in orofacial pain management.A comprehensive literature review was completed in the PubMed/MEDLINE, Embase, Cumulated Index to Nursing and Allied Health Literature, Dentistry and Oral Sciences Source Library databases up through June 17, 2019, using terms such as neurogenic, inflammation, naltrexone, temporomandibular, and chronic pain. The primary outcome was reduction in pain intensity and, secondarily, improvement in quality of life.A total of 793 studies were obtained with the initial search and 8 articles were selected for evaluation. Of these 8 articles, 4 were case reports, 3 were clinical studies, and 1 was a randomized controlled trial. Six studies included data on fibromyalgia, 2 studies included data on chronic regional pain syndrome, and 1 examined multiple diagnoses, including fibromyalgia, interstitial cystitis, and chronic pelvic pain. The primary outcome of all of the studies was pain intensity reduction.Low-dose naltrexone provides an alternative in medical management of chronic pain disorders as a novel anti-inflammatory and immunomodulator. It can offer additional management options, as orofacial pain conditions share characteristics with other chronic pain disorders. Owing to the size and heterogeneity of the studies, more large-scale studies are needed, along with additional studies assessing orofacial pain response to low-dose naltrexone.

The aim is to understand the concept of succession planning and its application to initiate successful succession planning in nursing education. In nursing education, there is a lack of qualified academic nursing administrators associated with a national nursing faculty shortage. Succession planning is often confused with other leadership management techniques. An understanding of the concept and its application is required to initiate successful succession planning in nursing education. Walker and Avant's methodological approach was followed for this concept analysis. The electronic databases searched included CINAHL, Medline, Google Scholar, PROQUEST, ERIC, PsycINFO, along with reference and bibliographic lists, relevant books, and public domain websites. The initial search terms included: succession planning, academic deans/directors, and nursing education. A pattern of five attributes emerged related to the characteristics of the concept of succession planning: organizational support and culture, attitude, commitment, and resources. Antecedents included strategic planning, identification of potential individuals, leadership development, mentoring programs, and identification of leadership competencies. Consequences of succession planning appeared to be related to retention, recruitment, improved leadership competencies, decreased role transition stress, and a healthier work environment. Succession planning has been defined as the proactive strategy involving the purposeful identification, assessment, and development of individuals through the processes of educating and mentoring for future leadership positions and establishing leadership continuity within an institution. Succession planning is needed for the continued growth and development academic nursing leaders.

Background Succession planning in nursing is a new concept with limited evidence found in nursing education. Purpose The purpose of this study was to provide a comprehensive summary of the descriptions of succession planning, as self-reported by administrators over an academic nursing division. Methods A qualitative descriptive methodology was utilized to obtain descriptions of succession planning from participants having personal experience with succession planning. Findings The categories discovered in the data included strategies for succession planning implementation, advantages of succession planning, and obstacles to succession planning. Discussion Succession planning can provide growth plans, leadership development, and mentoring programs allowing for positive relationships that cultivate, inspire, and assist faculty to develop the necessary skills to be successful in a leadership role. Succession planning requires adequate financial and human resources to develop potential leaders to meet the future needs of an organization, and ultimately, nursing education.

BACKGROUND: The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing. METHODS: Participants in an ongoing multi-site, prospective observational study completed the Pain Catastrophizing Scale (PCS) before and 12-weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models. RESULTS: Among the 165 RA patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (P

Objective Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high-throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine-based approach for patients with RA. Methods Rheumatologists at 6 US academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence-activated cell sorting, and RNA sequencing (RNA-seq). An optimized protocol for digesting synovial tissue was developed to generate high-quality RNA-seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters in RA patients. Results Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy. Conclusion Performance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high-quality samples for research. Through the use of cutting-edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine-based approach for patients with RA is attainable.

Objective. Pain sensitization may contribute to pain severity in rheumatoid arthritis (RA), impacting assessment of disease activity. We examined whether pain processing mechanisms were associated with disease activity among RA patients with active disease. Methods. This study includes 139 subjects enrolled in the Central Pain in Rheumatoid Arthritis cohort. Subjects underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at multiple sites, conditioned pain modulation, and temporal summation. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI) and its components. We examined cross-sectional associations between QST measures and disease activity using linear regression. Results. Low PPTs (high pain sensitization) at all sites were associated with high CDAI scores (P ≤ 0.03) and tender joint counts (P ≤ 0.002). Associations between PPTs and patient global assessments were also seen at most sites. High temporal summation at the forearm (also reflecting high pain sensitization) was significantly associated with high CDAI scores (P = 0.02), patient global assessment (P = 0.0006), evaluator global assessment (P = 0.01) and tender joint counts (P = 0.02). Conversely, conditioned pain modulation (a measure of descending inhibitory pain pathways) was only associated with tender joint count (P = 0.03). Conclusion. High pain sensitization is associated with elevations in disease activity measures. Longitudinal studies are underway to elucidate the cause-effect relationships between pain sensitization and inflammatory disease activity in RA. This article is protected by copyright. All rights reserved.

Purpose The purpose of this scoping review was to examine the range of literature about succession planning in nursing education. Background Succession planning establishes leadership continuity and inherent knowledge within an institution and nursing education. Most of the literature on succession in nursing is focused in the healthcare setting with limited information of succession planning in nursing education discovered. Method Arksey and O’Malley’s (2005) framework was used to guide this review. Results Emergent categories in the charted literature representing succession planning in nursing education included discouraging factors to assuming a leadership role, encouraging factors to assuming a leadership role, and strategies for successful succession planning. Conclusion There are many factors that discourage and encourage a faculty member when pursuing a leadership position. Developing and implementing a successful succession plan that includes the development of leadership abilities and traits could foster the development of future leaders in nursing education.

Background The authors aimed to evaluate the efficacy of low-dose naltrexone in the management of chronic pain conditions and determine its potential use in orofacial pain management. Methods A comprehensive literature review was completed in the PubMed/MEDLINE, Embase, Cumulated Index to Nursing and Allied Health Literature, Dentistry and Oral Sciences Source Library databases up through June 17, 2019, using terms such as neurogenic, inflammation, naltrexone, temporomandibular, and chronic pain. The primary outcome was reduction in pain intensity and, secondarily, improvement in quality of life. Results A total of 793 studies were obtained with the initial search and 8 articles were selected for evaluation. Of these 8 articles, 4 were case reports, 3 were clinical studies, and 1 was a randomized controlled trial. Six studies included data on fibromyalgia, 2 studies included data on chronic regional pain syndrome, and 1 examined multiple diagnoses, including fibromyalgia, interstitial cystitis, and chronic pelvic pain. The primary outcome of all of the studies was pain intensity reduction. Conclusions and Practical Implications Low-dose naltrexone provides an alternative in medical management of chronic pain disorders as a novel anti-inflammatory and immunomodulator. It can offer additional management options, as orofacial pain conditions share characteristics with other chronic pain disorders. Owing to the size and heterogeneity of the studies, more large-scale studies are needed, along with additional studies assessing orofacial pain response to low-dose naltrexone.

OBJECTIVE Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs). METHODS We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT. RESULTS Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02). CONCLUSION We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.

Scleroderma spectrum diseases are a heterogeneous group of disorders that are distinguished by abnormalities of the connective tissue in the skin and, in some cases, other organs. Each disorder may be characterized by the extent of cutaneous and internal involvement, as well as histopathologic features of skin biopsy. Scleroderma spectrum diseases include systemic scleroderma, localized scleroderma, and eosinophilic fasciitis. This chapter reviews the classification, epidemiology, etiology, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, outcome measures, management, and clinical course of scleroderma as well as the definition and classification, etiology/genetics, differential diagnosis, and treatment of localized scleroderma. Also discussed are the definition and classification, epidemiology, etiology/genetics/pathogenesis, diagnosis, differential diagnosis, and treatment of eosinophilic fasciitis. Tables review the classification of—and antinuclear antibodies in—scleroderma as well as the key assessments and interventions in scleroderma management. Figures illustrate the disease's presentation and clinical manifestations, including several images of scleroderma of the hands; face, palmar, and buccal telangiectasias in a patient with scleroderma; a radiograph demonstrating calcinosis of the elbow; Raynaud’s phenomenon; high-resolution computed tomographic images of diffuse cutaneous scleroderma, scleroderma and severe pulmonary hypertension, and limited cutaneous scleroderma; plus an esophagram demonstrating hypomotility. This review contains 11 highly rendered figures, 3 tables, and 72 references.

Objectives The study aimed to assess the burden of RA among the US Medicare population (aged ≥65 years) by comparing co-morbidities, health-care resource utilization (HCRU) and costs against matched non-RA Medicare patients. Methods Data were obtained from the Medicare fee-for-service claims database from 2010 to 2013. RA Medicare patients were identically matched with Medicare patients without RA (controls) based on demographics. Bivariate analyses were conducted to examine differences between cohorts for co-morbidities, HCRU and costs. A generalized linear model was used to test relationships between patient-level characteristics, HCRU and costs. Results The study population included 115 867 RA patients and 115 867 age-, sex-, race- and region-matched non-RA controls. Mean age was 75.2 years; 79.4% were female. Co-morbidities were greater in RA vs non-RA patients [Charlson Co-morbidity Index (excluding RA): 1.86 vs 1.00; P

BackgroundDespite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.MethodsWe randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.ResultsIn the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.ConclusionsMyeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Objective: Although pain in knee osteoarthritis (OA) commonly affects activity engagement, the daily pain experience has not been fully characterized. Specifically, the nature and impact of pain flares is not well understood. This study characterized pain flares as defined by participants with knee OA. Pain flare occurrence and experience were measured over 7 days. Methods: This was a multiple methods study; qualitative methods were dominant. Data were collected during the baseline portion of a randomized controlled trial. Participants met criteria for knee OA and had moderate to severe pain. They completed questionnaires and a 7-day home monitoring period that captured momentary symptom reports simultaneously with physical activity via accelerometry (n = 45). Participants also provided individual definitions of pain flare that were used throughout the home monitoring period to indicate whether a pain flare occurred. Results: Pain flares were described most often by quality (often sharp), followed by timing (seconds, minutes) and by antecedents and consequences. When asked if their definition of a flare agreed with a supplied definition, 49% of the sample reported only "somewhat," "a little," or "not at all." Using individual definitions, 78% experienced at least 1 daily pain flare over the home monitoring period; 24% had a flare on more than 50% of the monitored days. Conclusion: Pain flares were common, fleeting, and often experienced in the context of activity engagement. Participants' views on what constitutes a pain flare differ from commonly accepted definitions. Pain flares are an understudied aspect of the knee OA pain experience and require further characterization.

Objective To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. Methods SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. Results This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients ( p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR=0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption ( p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups ( p = 0.28). Conclusions In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

Objective.A variety of authorities in pain measurement and outcome methodology met prior to the Outcome Measures in Rheumatology (OMERACT) 12 meeting in May 2014 to develop partnerships for consensus on pain outcomes.Methods.Following overview presentations, discussion centered on pain-specific and global constructs in the domain of chronic pain. Practical issues for clinical trial implementation were also discussed. Breakout sessions were completed regarding additional details of domain constructs. A nominal group process involving all workshop participants confirmed that chronic pain outcome measures encompass a broad range of constructs and that existing scales may be inadequate for assessment in clinical trials.Results.Participants endorsed that both pain intensity and pain interference are important constructs to be measured in clinical trials of chronic pain as it pertains to rheumatologic diagnoses.Conclusion.Further work is needed on inclusion of the patient perspective in the development of pain domains as well as Cochrane Collaboration summary of findings tables.

Objective Aminopeptidase N/CD13 (EC 3.4.11.2) is a metalloproteinase expressed by fibroblast-like synoviocytes (FLS). It has been suggested that CD13 can act chemotactically for T cells in rheumatoid arthritis (RA). We undertook this study to measure CD13 in vivo and in vitro in RA samples and to determine whether CD13 could play a role in the homing of T cells to the RA joint. Methods Interleukin-17–treated FLS were used to immunize mice, from which a novel anti-human CD13 monoclonal antibody (mAb), 591.1D7.34, was developed. The mAb 591.1D7.34 and a second anti-CD13 mAb, WM15, were used to develop a novel enzyme-linked immunosorbent assay (ELISA) for CD13, and CD13 enzymatic activity was measured in parallel. Chemotaxis of cytokine-activated T cells was measured by a chemotaxis-under-agarose assay. Results We detected substantial amounts of CD13 in synovial fluid (SF), sera, FLS lysates, and culture supernatants by ELISA, with a significant increase in CD13 in RA SF when compared to osteoarthritis SF. CD13 accounted for most but not all of the CD13-like enzymatic activity in SF. Recombinant human CD13 was chemotactic for cytokine-activated T cells through a G protein–coupled receptor and contributed to the chemotactic properties of SF independently of enzymatic activity. Conclusion CD13 is released from FLS into culture supernatants and is found in SF. CD13 induces chemotaxis of cytokine-activated T cells, a T cell population similar to that found in RA synovium. These data suggest that CD13 could play an important role as a T cell chemoattractant, in a positive feedback loop that contributes to RA synovitis.

Immobilization devices serve several purposes in radiation oncology including improved positional reproducibility and decreased patient movement. If immobilization device beam attenuation is unaccounted for in the treatment planning process, planning target volume (PTV) coverage can be compromised. A retrospective case study was performed to evaluate beam attenuation from head and neck (HN) immobilization devices in volumetric-modulated arc therapy using the Eclipse treatment planning system and the Anisotropic Analytical Algorithm. Three facilities retrospectively evaluated 15 patients with various HN carcinomas. A test plan was created from each patient's existing plan in Eclipse to include immobilization devices in the dose calculation. Plan comparisons were performed using dose-volume histograms, which assessed the maximum dose, percentage of the PTV that received 95% of the prescription dose (V95), and dose covering 100% of the PTV (D100). The test plan normalization values were then adjusted to match the original PTV coverage. The maximum dose difference calculated ranged from 0.3% to 4.1%. The absolute difference in V95 coverage between the HN and the test plans ranged from 0.4% to 2.3%. The difference in the D100 was more statistically significant, reporting a range of 1.2% to 71.4%. Finally, to achieve the same PTV coverage as observed in the HN plan, an adjustment to the normalization value was needed, which required a change ranging from 0.1 to 7.7. Attenuation from immobilization devices, when unaccounted for, can cause a misrepresentation of the dose delivered to the PTV. It is not a standardized practice among institutions to include immobilization devices within the body contour for dose calculations. However, with the increasing use of volumetric-modulated arc therapy for treatment of the HN region, precision is of the utmost importance, and inclusion of immobilization devices should be standardized.

Pain is a prominent component of many rheumatologic conditions, and is the result of a complex physiologic interaction of central and peripheral nervous system signaling that results in a highly individualized symptom complex. Pain is frequently categorized as acute or chronic (generally greater than three months duration). Chronic pain is not simply acute pain that has lasted longer, and is more likely to be influenced by input from the central nervous system, whereas acute pain is often attributable primarily to inflammation and/or damage in peripheral structures (i.e., nociceptive input). The prominent role of central factors in chronic pain is highlighted by the fact that there is currently no chronic pain condition in which the degree of tissue inflammation or damage alone (e.g., as measured by radiographs, magnetic resonance imaging (MRI), or endoscopy) accurately predicts the presence or severity of pain. Central factors alter pain processing by setting the “gain”, such that when peripheral input is present, it is processed against a background of central factors that can enhance or diminish the experience of pain. There are very large inter-individual differences in these central nervous system factors that influence pain perception, such that some individuals with significant peripheral nociceptive input (e.g. from joint damage or inflammation) will feel little or no pain, whereas others are very pain sensitive, and they can experience pain with minimal or no identifiable abnormal peripheral nociceptive input. This emerging knowledge has important implications for pain management in individuals with chronic rheumatologic disorders.

Summary Background 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. Methods This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. Findings Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53–3·84) and 2·88 in the cyclophosphamide group (1·19–4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019). Interpretation Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. Funding National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

ObjectiveEarly diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs).MethodsWe developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT.ResultsSixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02).ConclusionWe have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.

Much is known about inflammation and peripheral damage associated with arthritic conditions. Less is known, however, about the pain that can accompany arthritis. Recent work has focused on activities within the central nervous system (CNS) such as central sensitization, higher order cortical pain processing, and deficiencies in descending neuromodulation to explain situations where arthritis pain seems discordant with the disease activity. These central mechanisms are also thought to account for many of the comorbid symptoms of chronic pain such as fatigue, sleep disturbance, cognitive disturbances, and mood disturbances. While traditional analgesics (e.g., NSAIDs opioids) may be appropriate for some aspects of arthritic pain, central pathology may be more responsive to agents such as serotonin–norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, and psychosocial interventions. A balance between peripheral and central factors likely influences the perception of pain in arthritis. Optimal disease management relies upon matching the appropriate treatment to the relevant mechanisms.

Dexmedetomidine (DMET) is a useful agent for sedation, both alone and in combination with other agents, in critically ill patients, including those on extracorporeal membrane oxygenation (ECMO) therapy. The drug is a clonidine-like derivative with an 8-fold greater specificity for the alpha 2-receptor while maintaining respiratory and cardiovascular stability. An in vitro ECMO circuit was used to study the effects of both “new” and “old” membrane oxygenators on the clearance of dexmedetomidine over the course of 24 hours. Once primed, the circuit was dosed with 840 μg of dexmedetomidine for a final concentration of 0.9 μg/ml. Serial samples, both pre- and post-oxygenator, were taken at 5, 60, 360, and 1440 minutes. Concentrations of the drug were expressed as a percentage of the original concentration remaining at each time point, both for new and old circuits. The new circuits were run at a standard flow for 24 hours, after which time the circuit was considered old and re-dosed with dexmedetomidine and the trial repeated. Results show that dexmedetomidine losses occur early in the circuits and then continue to decline. Initial losses in the first hour were 11+-65% and 59-73% pre- and post-oxygenator in the new circuit and 36-50% and 42-72% in the old circuit. The clearance of the drug through the membrane oxygenator exhibits no statistical difference between pre and post or new and old circuits. Dexmedetomidine can be expected to exhibit concentration changes during ECMO therapy. This effect appears to be more related to adsorption to the polyvinyl chloride (PVC) tubing rather than the membrane oxygenator. Dosage adjustments during dexmedetomidine administration during ECMO therapy may be warranted in order to maintain adequate serum concentrations and, hence, the desired degree of sedation.*(Lack of equilibrium)

Objective To examine the relationship between pain, radiographic severity, and a common set of co-occurring centrally-mediated symptoms (fatigue, sleep quality, and depression) in women with knee osteoarthritis. Methods Participants underwent knee radiographs, and had repeated assessments of pain severity and other centrally-mediated symptoms during a 5-day home monitoring period. To examine associations between pain severity (the average of pain over the home monitoring period), measures of osteoarthritis radiographic severity (Kellgren/Lawrence grade, minimum joint space width), centrally-mediated symptoms, and demographics (age) were used. Symptoms of fatigue, sleep efficiency, and depression were used in a composite measure representing centrally-mediated symptoms. Results Using a series of linear regression models in which each variable was entered hierarchically (n = 54), the final model showed that 27% of the variance in pain severity was explained by age, radiographic severity, and centrally-mediated symptoms. Centrally-mediated symptoms explained an additional 10% of the variance in pain severity after the other 2 variables were entered. Conclusion Both radiographic severity and centrally-mediated symptoms were independently and significantly associated with pain severity in women with knee osteoarthritis. In addition to more severe radiographic features, women with higher centrally-mediated symptoms had greater pain severity. Treatments for women with symptomatic knee osteoarthritis may be optimized by addressing both peripheral and central sources of pain.

Mechanisms underlying chronic pain differ from those underlying acute pain. In chronic pain states, central nervous system (CNS) factors appear to play particularly prominent roles. In the absence of anatomical causes of persistent pain, medical sub-specialities have historically applied wide-ranging labels (e.g., fibromyalgia (FM), irritable bowel syndrome, interstitial cystitis and somatisation) for what now is emerging as a single common set of CNS processes. The hallmark of these 'centrally driven' pain conditions is a diffuse hyperalgesic state identifiable using experimental sensory testing, and corroborated by functional neuroimaging. The characteristic symptoms of these central pain conditions include multifocal pain, fatigue, insomnia, memory difficulties and a higher rate of co-morbid mood disorders. In contrast to acute and peripheral pain states that are responsive to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, central pain conditions respond best to CNS neuromodulating agents, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants.

Rheumatoid arthritis (RA) affects 1-2% of the general population. Although often thought of as primarily a localized inflammatory disorder with associated joint destruction, it is a diffuse systemic disease. Extra-articular manifestations of rheumatoid arthritis can be demonstrated in almost 50% of patients with RA, and include pulmonary, cardiac, ocular, renal, hematologic, and neurologic involvement. In this article, we review recent studies of interstitial lung disease (ILD) in RA with a focus on clinical and pathological features of rheumatoid arthritis associated interstitial lung disease (RA-ILD). We discuss an approach to the diagnosis and treatment of RA-ILD including potential biomarkers, and conclude by outlining areas for future research.

Objective.Raynaud’s phenomenon (RP) is an important clinical feature of systemic sclerosis (SSc) for which consistently effective therapies are lacking. The study was designed to assess the safety, tolerability, and efficacy of tadalafil, a selective, long acting type V cyclic GMP phosphodiesterase (PDE-5) inhibitor, in this clinical syndrome.Methods.We performed a prospective, randomized, double-blind, placebo-controlled, crossover study comparing oral tadalafil at a fixed dose of 20 mg daily for a period of 4 weeks versus placebo in women with RP secondary to SSc.Results.Thirty-nine subjects completed the study and were evaluable. There were no statistically significant differences in Raynaud Condition Score (RCS), frequency of RP episodes, or duration of RP episodes between treatment groups. Placebo response was a confounding factor. Tadalafil was well tolerated.Conclusion.Tadalafil appears to be safe and well tolerated but lacks efficacy in comparison to placebo as a treatment for RP secondary to SSc.

At the pain workshop held prior to the Outcome Measures in Rheumatology (OMERACT) 12 conference, chronic nonmalignant pain (CP) as a “disease” was discussed, in response to growing interest in this concept and in terms of the effect on the OMERACT Filter 2.0 framework. CP is often assessed as a unidimensional outcome measure; however, if CP is a disease, then outcome measures need to define the disease state and identify all its manifestations as well as its effects, as specified by Filter 2.0. The aim was to write a discussion piece, reflecting the workshop contributions and debate, as an important step in opening a dialogue around future OMERACT Filter 2.0 Framework developments.

Objective.To assess the current state of reporting of pain outcomes in Cochrane reviews on chronic musculoskeletal painful conditions and to elicit opinions of patients, healthcare practitioners, and methodologists on presenting pain outcomes to patients, clinicians, and policymakers.Methods.We identified all reviews in the Cochrane Library of chronic musculoskeletal pain conditions from Cochrane review groups (Back, Musculoskeletal, and Pain, Palliative, and Supportive Care) that contained a summary of findings (SoF) table. We extracted data on reported pain domains and instruments and conducted a survey and interviews on considerations for SoF tables (e.g., pain domains, presentation of results).Results.Fifty-seven SoF tables in 133 Cochrane reviews were eligible. SoF tables reported pain in 56/57, with all presenting results for pain intensity (20 different outcome instruments), pain interference in 8 SoF tables (5 different outcome instruments), and pain frequency in 1 multiple domain instrument. Other domains like pain quality or pain affect were not reported. From the survey and interviews [response rate 80% (36/45)], we derived 4 themes for a future research agenda: pain domains, considerations for assessing truth, discrimination, and feasibility; clinically important thresholds for responder analyses and presenting results; and establishing hierarchies of outcome instruments.Conclusion.There is a lack of standardization in the domains of pain selected and the manner that pain outcomes are reported in SoF tables, hampering efforts to synthesize evidence. Future research should focus on the themes identified, building partnerships to achieve consensus and develop guidance on best practices for reporting pain outcomes.

Rheumatoid arthritis (RA) is a chronic disease that affects millions of patients worldwide. As better therapies emerge for treatment of this condition, patients with RA are living longer and are more likely to experience diseases associated with aging such as osteoporosis. The aetiology of osteoporosis in patients with RA is multifactorial, with some bone loss attributable to the underlying inflammatory disease. Patients may also experience bone loss that is a consequence of therapy with corticosteroids. Progress in the diagnosis and evaluation of osteoporosis has led to a greater awareness of this major health problem. There have also been many advances in our understanding of the pathophysiology of RA. However, recent studies have suggested that, despite our growing understanding of these diseases, therapies for preventing bone loss in this patient population are underutilised. Patients with RA, especially those taking corticosteroids or with persistent disease activity, must have their bone mass assessed with bone mineral density testing. RA patients with documented osteoporosis or those at high risk for the development of this potentially devastating complication should receive calcium and vitamin D supplementation as well as an anti-resorptive agent.

Post-transcriptional mechanisms play a critical role in regulating the expression of numerous proteins that promote inflammatory arthritis. The mRNAs encoding a subset of these proteins possess adenine/uridine-rich elements (AREs) in their 3′-untranslated regions that profoundly influence the rate at which mRNA is degraded and translated into protein. Tristetraprolin (TTP) and T cell intracellular antigen-1 (TIA-1) are ARE-binding proteins that dampen the expression of this class of proteins by promoting mRNA degradation and protein translation, respectively. We have discovered that TIA-1 and TTP function as arthritis-suppressor genes: TIA-1−/− mice develop mild arthritis, TTP−/− mice develop severe arthritis, and TIA-1−/−TTP−/− mice develop very severe arthritis. Paradoxically, lipopolysaccharide (LPS)-activated macrophages derived from TIA-1−/−TTP−/− macrophages produce less tumor necrosis factor α (TNF-α) than TIA-1−/− or TTP−/− macrophages. The bone marrows of these mice exhibit increased cellularity, reflecting the presence of mature neutrophils that secrete TNF-α in response to LPS stimulation. We hypothesize that TIA-1−/−TTP−/− neutrophils are a source of arthritigenic TNF-α, which promotes severe erosive arthritis in these mice.

Although pain in knee osteoarthritis (OA) commonly affects activity engagement, the daily pain experience has not been fully characterized. Specifically, the nature and impact of pain flares is not well understood. This study characterized pain flares as defined by participants with knee OA. Pain flare occurrence and experience were measured over 7 days.This was a multiple methods study; qualitative methods were dominant. Data were collected during the baseline portion of a randomized controlled trial. Participants met criteria for knee OA and had moderate to severe pain. They completed questionnaires and a 7-day home monitoring period that captured momentary symptom reports simultaneously with physical activity via accelerometry (n = 45). Participants also provided individual definitions of pain flare that were used throughout the home monitoring period to indicate whether a pain flare occurred.Pain flares were described most often by quality (often sharp), followed by timing (seconds, minutes) and by antecedents and consequences. When asked if their definition of a flare agreed with a supplied definition, 49% of the sample reported only "somewhat," "a little," or "not at all." Using individual definitions, 78% experienced at least 1 daily pain flare over the home monitoring period; 24% had a flare on more than 50% of the monitored days.Pain flares were common, fleeting, and often experienced in the context of activity engagement. Participants' views on what constitutes a pain flare differ from commonly accepted definitions. Pain flares are an understudied aspect of the knee OA pain experience and require further characterization.

Introduction Tumor necrosis factor (TNF ) is an important mediator of the molecular cascade that leads to chronic inflammation. It induces chemokine production, which results in the recruitment of leukocytes into the local environment, and upregulates adhesion molecules on vascular endothelial cells, which also promotes the localization of leukocytes into the inflamed tissue. Animal models suggest that TNF also plays an important role in the formation and maintenance of granulomas (1). Granulomas form in response to either infection or an inflammatory stimulus, and are composed of organized aggregations of activated macrophages surrounded by lymphocytes and fibroblasts (2). Fibroblasts surrounding the granuloma produce a fibrous capsule, and this tissue reaction may help protect the host from an inciting agent by maintaining containment and reducing the nutrient availability to potential infectious agents. Sensitized CD4 T cells with a Th1 pattern of cytokine production help initiate and maintain the structure, and cross-talk between T lymphocytes and macrophages is also important for maintenance. Both interferon gamma and TNF inhibit microbial growth, and have a synergistic effect on macrophage activation. Blockade of TNF results in down regulation of many adhesion molecules, and decreases circulating inflammatory cytokines. Etanercept is an anti–TNF therapy developed for the treatment of inflammatory arthritis. It is a fusion protein that consists of the extracellular ligandbinding domain of the TNF receptor coupled to the Fc portion of human IgG. It is thought to work by binding TNF and blocking its interaction with TNF receptors, thereby rendering TNF inactive. Chronic TNF inhibition has been rarely associated with reactivation of selected infections such as mycobacterial infections, which require granuloma formation for host response. Previous studies have suggested that anti–TNF therapy may result in diminished granuloma formation (3). For this reason anti–TNF therapy is being evaluated in sarcoidosis, a disease characterized by the formation of granulomas (4). Although much is known about the mediators involved in cytokine production in granulomatous diseases, the exact role of TNF remains unclear, as the following case illustrates. We report a patient who developed a pulmonary granulomatosis reaction (culture negative) while receiving etanercept therapy for psoriatic arthritis.

Objective.To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc).Methods.Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests.Results.Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003).Conclusion.Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.

Scleroderma (SSc) is characterized by Raynaud’s phenomenon, proliferative vascular lesions, and fibrosis of the skin and internal organs. The exact mechanism of tissue scarring is still unknown, however, the abnormal phenotype has been suggested to be due to excessive production of extracellular matrixes, such as collagen I (Col I), by fibroblasts (1). These cells proliferate rapidly, stain positive for α-smooth muscle actin, and therefore possess a myofibroblast phenotype (2). Platelet-derived growth factor (PDGF) and its receptor (PDGFR) have been suggested as key elements in fibrosis. Increased PDGF activity was observed in plasma-derived serum from patients with progressive SSc (3). Immunohistological study revealed increased expression of PDGF and PDGFR in SSc skin biopsies (4, 5). Cytokines such as transforming growth factor β (TGFβ) and interleukin-1α stimulate PDGFR expression and PDGF production in SSc fibroblasts, and appear to be critical for promoting fibrosis in SSc fibroblasts (6, 7). PDGF stimulates the Ras- ERK1/2- reactive oxygen species (ROS) signaling pathway and results in stimulation of Col gene expression (8). All these studies point to the importance of PDGFR signaling in the development of skin lesions in SSc. Reactive oxygen species such as superoxide (O2•−) act as messengers to maintain cellular functions through oxidation-reduction reaction (redox) signaling (9). However, when the production of ROS exceeds the cellular antioxidant capacity and disturbs the balance of the normal redox state, this can lead to oxidative damage of proteins, lipids, and DNA. Increased oxidative damage by ROS has been suggested in the pathogenesis of SSc (8, 10–14). The imbalance of the redox state can cause endothelial dysfunction and injury (15), fibroblast proliferation (16), increased Col synthesis (11), and favoring autoantibody production through a Th2 profile (17); all major characteristics of SSc. Free radical generators such as bleomycin can result in skin fibrosis similar to SSc (18), and in fact, bleomycin injected into mouse skin serves as an animal model of SSc (19). Recently an animal model for SSc has been established by injecting different forms of ROS subcutaneously (20). N-acetylcysteine (NAC), a thiol antioxidant, decreases O2•− production in vitro (11), and shows promising results in alleviating SSc symptoms (14, 21–23). NAC is also used as a treatment for idiopathic pulmonary fibrosis (24). These studies imply that there can be a thiol-oxidation mechanism involved in SSc oxidative stress, since NAC not only acts as a free radical scavenger (25), but also acts specifically on protein thiols to support glutathione synthesis (26) and generate free sulfhydryl groups (27). The protein tyrosine phosphatase (PTP) family is a critical regulator of a variety of cellular signaling pathways including the PDGFR. These PTPs act by dephosphorylating the activation signals elicited by protein tyrosine kinases. PTPs are characterized by their signature motif, HC(X)5R, which contains a cysteine (Cys) residue that is essential for their catalytic activity. The low pKa of this Cys residue allows it to function as a nucleophile, but also makes it susceptible to oxidation. Several studies have shown that the Cys residue is oxidized in the presence of ROS for various PTPs (28, 29). These observations imply that the increased ROS in SSc can oxidize PTPs that are involved in the PDGFR signaling pathway. In this study, we examined the effect of excessive oxidative stress on PTP1B, a phosphatase that has been shown to dephosphorylate the PDGFR (30, 31). The effect of the thiol antioxidant, NAC, on cellular ROS production, PDGFR phosphorylation, tyrosine-phosphorylated proteins, and PTP1B activity was also investigated.

Systemic sclerosis- (SSc-) related vasculopathy, as manifested by Raynaud's Phenomenon (RP) and digital ulcers (DUs), is associated with significant impairment of the quality of life and morbidity. The current vasoactive approach for SSc-RP, although employing vasodilators, is entirely off-label. PDE-5 inhibitors improve peripheral circulation, are well tolerated, and are widely used for various forms of constrictive vasculopathies. This class of medications has become one of the first lines of treatment of SSc-RP and SSc-DUs among rheumatologists that routinely treat SSc patients. Due to the lack of robust randomized clinical trials of PDE-5 inhibitors in SSc-RP/DUs, the PDE-5 inhibitors have not been FDA approved for these particular indications, which constitutes a significant barrier to prescribing this category of drugs. This paper reviews the current state of evidence-based knowledge in SSc-related vasculopathy and the use of PDE-5 inhibitors.

Objective.Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.Methods.Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival.Results.Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493).Conclusion.Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.

Interstitial lung disease is a common manifestation of systemic sclerosis, and often leads to death in these patients. These authors describe the case of a previously healthy woman with acute systemic sclerosis who experienced an unusually fulminant course of interstitial lung disease, which did not respond to treatment with intravenous cyclophosphamide. Background. A 36-year-old woman developed new-onset Raynaud phenomenon and rapidly progressive dyspnea over a 2-week period. A lung biopsy demonstrated pauci-inflammatory nonspecific pneumonitis, which proved refractory to systemic corticosteroid and intravenous cyclophosphamide therapy. Her preterminal course in an intensive care unit was typified by sequential organ failure. Postmortem examination showed extensive organ fibrosis, including severe diffuse alveolar damage and parenchymal fibrosis, and a notable lack of potentially treatable tissue inflammation. Investigations. Chest radiography, physical examination, screening for autoantibodies, measurement of serum creatinine, creatine phosphokinase, and brain natriuretic peptide levels, cardiac examination, pulmonary function tests, electrocardiography, transthoracic Doppler echocardiography, right heart catheterization, high-resolution thoracic CT, pulmonary ventilation/perfusion scan, lung biopsy. Diagnosis. Interstitial lung disease associated with diffuse systemic sclerosis. Management. Treatment with oxygen, oral and intravenous corticosteroids, mycophenolate mofetil and intravenous cyclophosphamide.

TIA-1 and TTP are AU-rich element-binding proteins that prevent the pathological overexpression of tumor necrosis factor α (TNF-α). TIA-1 inhibits the translation of TNF-α transcripts, whereas TTP promotes the degradation of TNF-α transcripts. Here we show that TIA-1 and TTP function as arthritis suppressor genes: TIA-1 –/– mice develop mild arthritis, TTP –/– mice develop severe arthritis, and TIA-1 –/– TTP –/– mice develop very severe arthritis. Peritoneal macrophages derived from all three genotypes overexpress cyclooxygenase 2 and TNF-α. Surprisingly, lipopolysaccharide-activated TIA-1 –/– TTP –/– macrophages secrete less TNF-α protein than either TIA-1 –/– or TTP –/– macrophages. In these mice, arthritogenic cytokine may be produced by neutrophils that accumulate in the bone marrow and peripheral blood. Our results suggest that TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritogenic cytokines.