RNA Virus Gene Signatures Detected in Patients With Cardiomyopathy After Chemotherapy; A Pilot Study.

Background: Viral infections are pervasive and leading causes of myocarditis. Immune-suppression after chemotherapy increases opportunistic infections, but the incidence of virus-induced myocarditis is unknown. Objective: An unbiased, blinded screening for RNA viruses was performed after chemotherapy with correlation to cardiac function. Methods: High-throughput sequencing of RNA isolated from blood samples was analyzed following chemotherapy for hematological malignancies (N = 28) and compared with left ventricular ejection fraction (LVEF). Results: On initial rigorous analysis, low levels of influenza orthomyxovirus and avian paramyxovirus sequences were detectable, but without significant correlation to LVEF (r = 0.208). A secondary broad data mining analysis for virus sequences, without filtering human sequences, detected significant correlations for paramyxovirus with LVEF after chemotherapy (r = 0.592, P < 0.0096). Correlations were similar for LVEF pre- and post- chemotherapy for orthomyxovirus (R = 0.483, P < 0.0421). Retrovirus detection also correlated with LVEF post (r = 0.453, p < 0.0591), but not pre-chemotherapy, but is suspect due to potential host contamination. Detectable phage and anellovirus had no correlation. Combined sequence reads (all viruses) demonstrated significant correlation (r = 0.621, P < 0.0078). Reduced LVEF was not associated with chemotherapy (P = NS). Conclusions: This is the first report of RNA virus screening in circulating blood and association with changes in cardiac function among patients post chemotherapy, using unbiased, blinded, high-throughput sequencing. Influenza orthomyxovirus, avian paramyxovirus and retrovirus sequences were detectable in patients with reduced LVEF. Further analysis for RNA virus infections in patients with cardiomyopathy after chemotherapy is warranted.

Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, ß1-4 Branching, ß1-6 Branching, and α2-6 Sialylation in Cancer.

Glycans represent a promising but only marginally accessed source of cancer markers. We previously reported the development of a molecularly bottom-up approach to plasma and serum (P/S) glycomics based on glycan linkage analysis that captures features such as α2-6 sialylation, ß1-6 branching, and core fucosylation as single analytical signals. Based on the behavior of P/S glycans established to date, we hypothesized that the alteration of P/S glycans observed in cancer would be independent of the tissue in which the tumor originated yet exhibit stage dependence that varied little between cancers classified on the basis of tumor origin. Herein, the diagnostic utility of this bottom-up approach as applied to lung cancer patients (n = 127 stage I; n = 20 stage II; n = 81 stage III; and n = 90 stage IV) as well as prostate (n = 40 stage II), serous ovarian (n = 59 stage III), and pancreatic cancer patients (n = 15 rapid autopsy) compared to certifiably healthy individuals (n = 30), nominally healthy individuals (n = 166), and risk-matched controls (n = 300) is reported. Diagnostic performance in lung cancer was stage-dependent, with markers for terminal (total) fucosylation, α2-6 sialylation, ß1-4 branching, ß1-6 branching, and outer-arm fucosylation most able to differentiate cases from controls. These markers behaved in a similar stage-dependent manner in other types of cancer as well. Notable differences between certifiably healthy individuals and case-matched controls were observed. These markers were not significantly elevated in liver fibrosis. Using a Cox proportional hazards regression model, the marker for α2-6 sialylation was found to predict both progression and survival in lung cancer patients after adjusting for age, gender, smoking status, and stage. The potential mechanistic role of aberrant P/S glycans in cancer progression is discussed.

Serum Immune Profiling for Early Detection of Cervical Disease.

BACKGROUND: The most recent (2012) worldwide estimates from International Agency for Research on Cancer indicate that approximately 528,000 new cases and 270,000 deaths per year are attributed to cervical cancer worldwide. The disease is preventable with HPV vaccination and with early detection and treatment of pre-invasive cervical intraepithelial neoplasia, CIN. Antibodies (Abs) to HPV proteins are under investigation as potential biomarkers for early detection. METHODS: To detect circulating HPV-specific IgG Abs, we developed programmable protein arrays (NAPPA) that display the proteomes of two low-risk HPV types (HPV6 and 11) and ten oncogenic high-risk HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52 and 58). Arrays were probed with sera from women with CIN 0/I (n=78), CIN II/III (n=84), or invasive cervical cancer (ICC, n=83). RESULTS: Abs to any early (E) HPV protein were detected less frequently in women with CIN 0/I (23.7%) than women with CIN II/III (39.0%) and ICC (46.1%, p<0.04). Of the E Abs, anti-E7 Abs were the most frequently detected (6.6%, 19.5%, and 30.3%, respectively). The least frequently detected Abs were E1 and E2-Abs in CIN 0/I (1.3%) and E1-Abs in CIN II/III (1.2%) and ICC (7.9%). HPV16-specific Abs correlated with HPV16 DNA detected in the cervix in 0% of CIN 0/I, 21.2% of CIN II/III, and 45.5% of ICC. A significant number (29 - 73%) of E4, E7, L1, and L2 Abs had cross-reactivity between HPV types. CONCLUSION: HPV protein arrays provide a valuable high-throughput tool for measuring the breadth, specificity, and heterogeneity of the serologic response to HPV in cervical disease.

Comprehensive appraisal of magnetic resonance imaging findings in sustained rheumatoid arthritis remission: a substudy.

OBJECTIVE: To evaluate the effect of sustained American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission on residual joint inflammation assessed by magnetic resonance imaging (MRI) and to secondarily evaluate other clinical definitions of remission, within an early seropositive rheumatoid arthritis (RA) cohort. METHODS: A subcohort of 118 RA patients was enrolled from patients who completed the 2-year, double-blind randomized Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. Patients received a single contrast-enhanced 1.5T MRI of their most involved wrist. Two readers scored MRIs for synovitis, osteitis, tenosynovitis, and erosions. Clinical assessments were performed every 3 months during the trial and at time of MRI. RESULTS: The subcohort was 92% seropositive with mean age 51 years, duration 4.1 months, and Disease Activity Score in 28 joints using the erythrocyte sedimentation rate 5.8 at TEAR entry. Total MRI inflammatory scores (tenosynovitis + synovitis + osteitis) were lower among patients in clinical remission. Lower MRI scores were correlated with longer duration of Clinical Disease Activity Index (CDAI) remission (ρ = 0.22, P = 0.03). At the time of MRI, 89 patients had no wrist pain/tenderness/swelling; however, all 118 patients had MRI evidence of residual joint inflammation after 2 years. No statistically significant differences in damage or MRI inflammatory scores were observed across treatment groups. CONCLUSION: This is the first detailed appraisal describing the relationship between clinical remission cut points and MRI inflammatory scores within an RA randomized controlled trial. The most stringent remission criteria (2011 ACR/EULAR and CDAI) best differentiate the total MRI inflammatory scores. These results document that 2 years of triple therapy or tumor necrosis factor plus methotrexate treatment in early RA does not eliminate MRI evidence of joint inflammation.

Changes in right heart haemodynamics and echocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis.

BACKGROUND: Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype. METHODS: Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil. RESULTS: 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm(2)), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340). CONCLUSIONS: PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.

Prevalence of subclinical atherosclerosis is increased in systemic sclerosis and is associated with serum proteins: a cross-sectional, controlled study of carotid ultrasound.

OBJECTIVES: SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS. METHODS: Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure. RESULTS: Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001). CONCLUSION: Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.

Associations between a scleroderma-specific gastrointestinal instrument and objective tests of upper gastrointestinal involvements in systemic sclerosis.

OBJECTIVES: UCLA-SCTC-GIT 2.0 is an instrument designed to evaluate gastrointestinal (GI) symptoms in systemic sclerosis (SSc). The objective of our study was to assess the associations between the upper GI (UGI) symptom scales (reflux and distention/bloating [D/B] scales) versus objective/laboratory studies. METHODS: Fifty-five patients with SSc were enrolled at 2 centres. Each patient completed the GIT 2.0 and had objective and laboratory tests. Correlations were assessed using the Spearman's test. We also assessed the average scores in patients with positive vs. negative tests and compared them using the t-test and Wilcoxon test. RESULTS: The mean (SD) age was 53.6 (11.8), 90% were women and 49% had limited SSc. The mean reflux and D/B scores were 0.82 and 1.25, respectively (moderate severity). The reflux scale had moderate correlations with upper GI objective evaluations (correlation coefficient ≥0.40) and was able to differentiate between patients with endoscopy proven esophagitis and manometric abnormalities (p=0.01 for both). D/B scores were numerically higher in patients with abnormal objective tests. The GIT 2.0 reflux and D/B scales had a high sensitivity ranging from 80% to 94% but very low specificity (range; 0-20%) based on objective gold standard GI measures. CONCLUSIONS: The GIT 2.0 reflux and D/B scales have a high sensitivity (range 80-94%) for UGI involvement. The GIT 2.0 instrument complements the objective tests for assessment of the UGI.

Combination of echocardiographic and pulmonary function test measures improves sensitivity for diagnosis of systemic sclerosis-associated pulmonary arterial hypertension: analysis of 2 cohorts.

OBJECTIVE: To evaluate routinely collected non-invasive tests from 2 systemic sclerosis (SSc) cohorts to determine their predictive value alone and in combination versus right heart catheterization (RHC)-confirmed pulmonary arterial hypertension (PAH). METHODS: We evaluated 2 cohorts of patients who were at risk or with incident PAH: (1) The Pulmonary Hypertension Assessment and Recognition Outcomes in Scleroderma (PHAROS) cohort and (2) an inception SSc cohort at Cochin Hospital, Paris, France. Estimated right ventricular systolic pressure (eRVSP) as determined by transthoracic echocardiogram (TTE) and pulmonary function test (PFT) measures was evaluated, and the predictive values determined. We then evaluated patients with PAH missed on TTE cutoffs that were subsequently identified by a PFT measure. RESULTS: In the PHAROS cohort (n = 206), 59 (29%) had RHC-defined PAH. An eRVSP threshold of 35-50 mm Hg failed to diagnose PAH in 7% to 31% of patients, 50% to 70% of which (n = 2-13) were captured by PFT measures. In the Cochin cohort (n = 141), 10 (7%) patients had RHC confirmed PAH. An eRVSP threshold of 35-50 mm Hg missed 0% to 70% (n = 0-7) of patients, of which 0% to 68% (n = 0-6) were met by PFT measures. The combination of TTE and PFT improved the negative predictive value for diagnosing PAH. CONCLUSION: In 2 large SSc cohorts, screening with TTE and PFT captured a majority of patients with PAH. TTE and PFT complement each other for the diagnosis of PAH.

Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the impact of comorbidities on achieving remission by examining changes in the clinical disease activity index (CDAI) in RA patients in the community-based Consortium of Rheumatology Researchers of North America (CORRONA) registry. METHODS: A subcohort of 1548 RA subjects with varying disease duration met the following inclusion criteria: started a DMARD/biologic agent, continued therapy ≥ 3 months, CDAI ≥ 2.8 at study entry and followed longitudinally from baseline to follow-up (mean time 7.46 months). Patients reported comorbidities according to a standardized list of 33 conditions. Entry characteristics were compared across age categories using one-way analysis of variance. Linear and logistic regression models were constructed to assess characteristics [e.g. age, disease duration, number of previous DMARDs/biologics, baseline modified health assessment questionnaire (MHAQ), baseline CDAI and number of comorbidities] associated with primary outcomes: change in CDAI (baseline to follow-up) and CDAI remission (yes/no). RESULTS: Although disease activity measures at entry were similar across age categories, older patients had more comorbidities, less improvement in CDAI/MHAQ and were less likely to attain remission at follow-up. However, after adjusting covariates an increasing number of patient-reported comorbidities and higher baseline CDAI (but not age) were consistently and independently associated with a lower likelihood of clinical improvement or remission (P < 0.001). CONCLUSION: In this observational cohort of community RA patients an increasing number of patients reported comorbidities, independently correlated with less CDAI improvement over time. These results reaffirm that comorbidities may be an important factor in consideration of treat-to-target recommendations and aid in understanding achievable RA therapeutic goals.

Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus.

INTRODUCTION: Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity. METHODS: cOPN and cNGAL were measured in prospectively followed pSLE (n=42) and adult SLE (aSLE; n=23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI). RESULTS: Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P=0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r=0.51 and 0.52, P=0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P=0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P=0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%). CONCLUSION: High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.

Evaluation of test characteristics for outcome measures used in Raynaud's phenomenon clinical trials.

OBJECTIVE: Randomized controlled trials (RCTs) in Raynaud's phenomenon (RP) have shown conflicting efficacy data. Also, there is no consensus on the outcome measures that should be used. Our objectives were to assess the reliability of individual core set measures used in 3 RCTs, evaluate the placebo response for individual core set measures, and determine if a composite of individual core set measures will decrease the placebo response, which may improve our ability to see treatment effects in future trials. METHODS: We analyzed core set measures from 249 patients in the placebo-treated groups from 3 RCTs. Core set measures analyzed included the Raynaud's Condition Score (RCS); patient and physician assessment of RP; pain, numbness, and tingling during an RP attack; average number of attacks/day; and duration of attacks. Intraclass correlation coefficients (ICCs) were calculated during the run-in period to the RCTs. RESULTS: ICCs of ≥0.70 were observed for the RCS, attack symptoms, and average attacks/day. A high placebo response rate was observed for all individual core measures except the duration of attacks. For the RCS, the placebo response ranged from 56% with ≥10% improvement to 19.5% with ≥60% improvement. In contrast, placebo response rates of 10-20% were observed when several core set measures were combined to develop a composite score. CONCLUSION: Outcome measures used in RCTs of RP are associated with marked variability. A combination of outcome measures is associated with low placebo responses. Future studies are needed to assess if a composite score will be able to differentiate placebo from an effective agent.

Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry.

BACKGROUND: Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21-24 mm Hg) are "at risk" of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics. METHODS: PHAROS is a multicentre prospective longitudinal cohort of patients with SSc "at risk" or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups. RESULTS: 206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS). CONCLUSIONS: Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.

Feasibility and construct validity of PROMIS and "legacy" instruments in an academic scleroderma clinic.

OBJECTIVE: The National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) roadmap initiative is a cooperative group program of research designed to develop, evaluate, and standardize item banks to measure patient-reported outcomes relevant across medical conditions. The objective of the current study was to assess feasibility and evaluation of the construct validity of PROMIS item banks versus legacy measures in an observational study in systemic sclerosis (SSc). We hypothesized that the PROMIS item banks can be administered in a clinical setting if there is adequate staff support without disrupting the flow of clinic. METHODS: Patients with SSc in a single academic center completed computerized adaptive test (CAT) administered PROMIS item banks during the clinic visit and legacy measures (using paper and pencil). The construct validity of PROMIS items was evaluated by examining correlations with corresponding legacy measures using multitrait-multimethod analysis. RESULTS: Participants consisted of 143 SSc patients with an average age of 51.5 years; 71% were female and 68% were white. The average number of items completed for each CAT-administered item bank ranged from 5 to 8 (69 CAT items per patient), and the average time to complete each CAT-administered item bank ranged from 48 seconds to 1.9 minutes per patient (average time = 11.9 minutes/per patient for 11 banks). All correlations between PROMIS domains and respective legacy measures were large and in the hypothesized direction (ranged from 0.61 to 0.82). CONCLUSION: Our study supports the construct validity of the CAT-administered PROMIS item banks and shows that they can be administered successfully in a clinic with support staff. Future studies should assess the feasibility of PROMIS item banks in a busy clinical practice.

Work productivity in scleroderma: analysis from the University of California, Los Angeles scleroderma quality of life study.

OBJECTIVE: To examine the productivity of patients with scleroderma (systemic sclerosis [SSc]) both outside of and within the home in a large observational cohort. METHODS: One hundred sixty-two patients completed the Work Productivity Survey. Patients indicated whether or not they were employed outside of the home, how many days per month they missed work (employment or household work) due to SSc, and how many days per month productivity was decreased by ≥50%. Patients also completed other patient-reported outcome measures. We developed binomial regression models to assess the predictors of days missed from work (paid employment or household activities). The covariates included: type of SSc, education, physician and patient global assessments, Health Assessment Questionnaire (HAQ) disability index (DI), Functional Assessment of Chronic Illness Therapy-Fatigue, and Center of Epidemiologic Studies Depression Scale Short Form. RESULTS: The mean age of patients was 51.8 years and 52% had limited cutaneous SSc. Of the 37% of patients employed outside of the home, patients reported missing 2.6 days per month of work and had 2.5 days per month of productivity reduced by half. Of the 102 patients who were not employed, 39.4% were unable to work due to their SSc. When we assessed patients for household activities (n = 162), patients missed an average of 8 days of housework per month and had productivity reduced by an average of 6 days per month. In the regression models, patients with lower education and poor assessment of overall health by a physician were more likely to miss work outside of the home. Patients with limited cutaneous SSc and high HAQ DI scores were more likely to miss work at home. CONCLUSION: SSc has a major impact on productivity at home and at work. Nearly 40% of patients reported disability due to their SSc.

Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4(+) T cells in the broncho-alveolar lavage of patients with systemic sclerosis.

T cells, particularly those producing IL-4, are implicated in inflammation-mediated fibrosis. In our phase I/IIa open-label pilot study in 15 patients with scleroderma-interstitial lung disease (SSc-ILD), high-dose imatinib treatment showed modest improvement in lung function and skin score, but with several adverse events. Here, we investigated T cell phenotype and cytokine production in bronchoalveolar lavage (BAL) from patients enrolled in this trial. We found that IL-4(+) T cells showed a stronger correlation with ground glass opacity (GGO) than fibrosis scores on lung high-resolution computer tomography scans. Frequencies of IL-4(+) T cells also discriminated patients with high (≥20) versus low (<20) GGO scores. Functional annotation clustering of proteins that correlated with T cells identified two major clusters that belonged to immune/inflammatory and wounding response. Repeat analyses after 1 year of treatment in 10 BAL samples, one each from the right middle and lower lobes of lung from 5 patients, showed that post-imatinib, IL-4(+) T cells were profoundly reduced but CD4(+) T cells increased, except in one patient who showed worsening of SSc-ILD. Post-imatinib increase in CD4(+) T cells correlated with soluble ICAM-3 and PECAM-1 levels in BAL, which associated with the lack of worsening in SSc-ILD. Thus, imatinib might confer its therapeutic effect in fibrosis via re-directing T cell responses from type 2 to other, non-type 2 cytokine producing CD4(+) T cells.

Minimally important differences of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.

OBJECTIVE: To provide minimally important difference (MID) estimates for the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) in a longitudinal observational cohort. METHODS: We administered the UCLA SCTC GIT 2.0 to 115 patients with systemic sclerosis (SSc) at 2 timepoints 6 months apart. The UCLA SCTC GIT 2.0 has 7 multi-item scales: Reflux, Distension/Bloating, Diarrhea, Fecal Soilage, Constipation, Emotional Well-being, and Social Functioning and a total GIT score. All scales are scored from 0 [better health-related quality of life (HRQOL)] to 3 (worse HRQOL) except the diarrhea and constipation scales (ranges 0-2 and 0-2.5, respectively). Patients also rated their overall and upper and lower GIT involvement during the second visit using a response scale with options "much better; somewhat better; almost the same; somewhat worse; or much worse." The minimally changed group was defined by those reporting they were somewhat better or somewhat worse compared to first visit. RESULTS: Study participants were 84% female and 81% white with a mean disease duration of 6.9 years. The MID estimates for improvement ranged from 0.07 for the Social Functioning scale to 0.36 for the Emotional Well-being scale. For worsening, the MID estimates ranged from 0.06 for the Fecal Soilage scale to 0.21 for the Social Functioning scale. CONCLUSION: We provide MID estimates for the UCLA SCTC GIT 2.0 scales. This information can aid in interpreting scale scores in future randomized controlled trials and observational studies.

A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease.

OBJECTIVE: Transforming growth factor ß (TGFß) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFß and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy. METHODS: We recruited 20 SSc patients with a forced vital capacity (FVC) of <85% predicted, dyspnea on exertion, and presence of a ground-glass appearance on high-resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy. RESULTS: The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P < 0.001). CONCLUSION: Use of high-dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.

Development and validation of French version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.

OBJECTIVES: The UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA-SCTCGIT) 2.0 was developed to assess systemic sclerosis (SSc) associated gastrointestinal tract (GIT) symptoms severity and its impact on patients' well-being. Our objective was to translate the UCLA-GIT 2.0 from English to French and to evaluate the reliability and validity of the French version. METHODS: UCLA-GIT 2.0 was adapted into French using a formal forward-backward translation method and administered to 76 French speaking patients with SSc. The patients also completed the SF-36. We evaluated the internal consistency reliability and construct validity by exploring associations between the UCLA SCTC GIT 2.0 and SF-36 scales. Patients were also classified into two groups based on unintended weight loss within the past 6 months (≥5% vs. <5% of total body weight). RESULTS: Participants were mostly white (90%), female (81%) and had limited SSc (50%). Mean score of the UCLA-GIT 2.0 scales were: 0.35 for faecal soilage, 0.44 for diarrhoea, 0.45 for emotional well-being, 0.48 for both constipation and social functioning, 0.52 for reflux, and 0.95 for distension/bloating. The instrument had acceptable reliability (defined as Cronbach alpha≥0.69) except for the diarrhoea scale (alpha=0.56). The majority of hypothesized correlations were of moderate magnitude (coefficient≥0.30) and were in the appropriate direction. Patients with ≥5% unintended weight loss had worse UCLA-GIT scores in all scales (p<0.05 for distention/bloating scale). CONCLUSIONS: The French version of the UCLA-GIT 2.0 has acceptable psychometric properties and can be used in French speaking SSc patients.

Quality indicator set for systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is associated with a marked economic burden, high treatment costs and decreased productivity. Although treatment strategies for SSc can have a substantial effect on patients' outcomes, it is not known whether patients with SSc consistently receive such care. Evaluation of process-of-care quality requires specification of quality indicators (QIs), clinically detailed statements of the eligible patients and the care they should receive to achieve a minimal level of quality of care. Our objective was to develop QIs for patients with SSc. METHODS: We performed a comprehensive literature review of diagnosis and treatment of SSc and proposed QIs that were evaluated by a national Expert Panel (n=9) who were asked to review the supporting literature and individually rank the validity of each QI. These rankings formed the basis of discussion at a face-to-face meeting following the RAND/UCLA method to integrate expert opinion with literature review to identify a set of final QIs. We then presented these QIs to members of the Scleroderma Clinical Trials Consortium (SCTC). RESULTS: Thirty-two QIs for SSc care were judged valid by the Expert Panel. The QI set includes 9 QIs for newly diagnosed with SSc, 12 follow-up QIs for management of SSc, and 11 treatment QIs. The SCTC experts agreed with the validity of each of the 32 QI and agreed that for all but one QI the specified tests, procedures and treatments recommended in the QI were generally available. CONCLUSIONS: We have developed 32 QIs for SSc using a rigorous methodology that can be employed to evaluate and improve care for patients with SSc, as well as inform policy decisions supporting appropriate care for SSc patients.