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author:("iranian, Paul")
1.  Prevalence of subclinical atherosclerosis is increased in systemic sclerosis and is associated with serum proteins: a cross-sectional, controlled study of carotid ultrasound 
Rheumatology (Oxford, England)  2013;53(4):704-713.
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.
PMCID: PMC4042927  PMID: 24357811
systemic sclerosis; atherosclerosis; serum proteins; endothelial dysfunction; type I interferon; carotid intima media thickness
2.  Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis 
Rheumatology (Oxford, England)  2013;52(10):1809-1817.
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.
PMCID: PMC3775293  PMID: 23813577
comorbidities; rheumatoid arthritis; age; remission
3.  Combination of Echocardiographic and Pulmonary Function Test Parameters Improves Sensitivity for the Diagnosis of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension- Analysis of Two Cohorts 
The Journal of rheumatology  2013;40(10):1706-1711.
To evaluate routinely collected non-invasive tests from two systemic sclerosis (SSc) cohorts to determine their predictive value alone and in combination vs. right heart catheterization (RHC)- confirmed pulmonary arterial hypertension (PAH).
We evaluated two 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. Estimated right ventricular systolic pressure (eRVSP) on echocardiogram (TTE) and and pulmonary function tests (PFT) parameters were evaluated and their predictive values determined. We then evaluated patients with PAH missed on TTE cutoffs that were subsequently identified by a PFT parameter.
In the PHAROS cohort (N=206), 59 (29%) had RHC-defined PAH. An eRVSP threshold of 35–50mmHg failed to diagnose PAH in 7–31% of patients, 50–70% of which (N=2–13) were captured by PFT parameters. In the Cochin cohort (N=141), 10 (7%) patients had RHC confirmed PAH. An eRVSP threshold of 35–50mmHg missed 0–70% (N = 0–7) patients, of which 0–68% (N = 0–6) were captured by PFT parameters. The combination of TTE and PFT improved the negative predictive value for diagnosing PAH.
In 2 large SSc cohorts, screening with TTE and PFT captured majority of patients with PAH. TTE and PFT complement each other for the diagnosis of PAH.
PMCID: PMC3798032  PMID: 23950183
Echocardiogram; Pulmonary Function Tests; Screening; Diagnosis; Systemic Sclerosis; Pulmonary Hypertension; Pulmonary Arterial Hypertension
4.  Evaluation of test characteristics for outcome measures used in Raynaud's phenomenon clinical trials 
Arthritis care & research  2013;65(4):630-636.
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: 1) assess the reliability of individual core set measures used in 3 RCTs; 2) evaluate the placebo response for individual core set measures; and 3) 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.
Patients and Methods
We analyzed core set measures from 249 patients in the placebo-treated groups from 3 RCTs. Core set measures analyzed included 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. ICC correlation coefficients were calculated during the run-in period to the RCTs.
ICC coefficients of ≥0.70 were observed for 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 20% 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.
Outcome measures used in RP RCTs are associated with marked variability. 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.
PMCID: PMC3529989  PMID: 22972592
Raynaud 's phenomenon; Composite Response Index; systemic sclerosis; primary Raynaud's phenomenon; secondary Raynaud's phenomenon
5.  Quality indicator set for systemic sclerosis 
Clinical and experimental rheumatology  2011;29(2 0 65):S33-S39.
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.
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).
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.
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.
PMCID: PMC3887520  PMID: 21586216
Systemic sclerosis; quality indicator
6.  Baseline Characteristics and Follow up in Patients with Normal Hemodynamics vs. Borderline Mean Pulmonary Arterial Pressure in Systemic Sclerosis — Results from the PHAROS Registry 
Annals of the Rheumatic Diseases  2012;71(8):1335-1342.
Patients with normal (mean pulmonary arterial pressure ≤20 mmHg) and borderline mean pulmonary pressures (mPAP) (boPAP; 21–24 mmHg) are “at risk” of developing pulmonary hypertension(PH). The objectives of this analysis were 1)to examine the baseline characteristics in systemic sclerosis(SSc) with Normal and boPAP, and 2) to explore long term outcomes in SSc patients with boPAP vs. Normal hemodynamics.
PHAROS is a multicenter prospective longitudinal cohort of patients with SSc “at risk” or recently diagnosed with resting PH on right heart catheterization (RHC). Baseline clinical characteristics, pulmonary function tests, high resolution computed tomography(HRCT), 2-D echocardiogram, and RHC results were analyzed in Normal and boPAP groups.
A total of 206 patients underwent RHC (35 Normal, 28 boPAP, 143 had resting PH). There were no differences in the baseline demographics. Patients in the boPAP group were more likely to have restrictive lung disease (67% vs. 30%), fibrosis on HRCT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs. 36.2mmHg; p<0.05) than patients with Normal hemodynamics. RHC revealed higher pulmonary vascular resistance (PVR) and more elevated mPAP on exercise(mPAP ≥30; 88% vs. 56%) in the boPAP 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 boPAP group and 32% of the Normal group developed resting PH (p=NS).
Patients with boPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and presence of exercise mPAP ≥30mmHg.
PMCID: PMC3398226  PMID: 22307943
Pulmonary hypertension; Systemic sclerosis; Borderline; Pulmonary hemodynamics
7.  A Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human Relaxin in the Treatment of Systemic Sclerosis with Diffuse Scleroderma 
Arthritis and rheumatism  2009;60(4):1102-1111.
A phase II randomized controlled trial of recombinant human relaxin suggested that 25 ug/kg/day was safe and clinically effective in improving skin disease and functional disability in scleroderma. We report the results of a large randomized, double-blind, placebo-controlled clinical trial comparing placebo with recombinant human relaxin, 10 ug/kg of body weight per day and 25 ug/kg per day, given for 24 weeks in patients with stable, diffuse, moderate to severe scleroderma (SSc).
Men and women 18 to 70 years of age with diffuse SSc, disease duration ≤ 5 years since the onset of the first non-Raynaud sign or symptom, a baseline modified Rodnan skin score (MRSS) of 20 or greater, or at least 16 if truncal involvement was present. Recombinant human relaxin (10 or 25 ug/kg/day), or placebo was administered for 24 weeks as a continuous subcutaneous infusion and there was a follow-up safety visit at week 28.
The primary outcome measure, the MRSS, was similar between the 3 groups at baseline and at weeks 4, 12, and 24 (P=NS). Secondary outcomes such as functional disability were similar in all 3 groups and the forced vital capacity significantly decreased in the relaxin groups (p< 0.04). The discontinuation of relaxin (both doses) at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as either doubling of baseline serum creatinine, renal crisis, or grade 3 or 4 hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo (p=0.04).
Recombinant relaxin was not significantly better than placebo in improving total skin score, pulmonary function, or functional disability in patients with diffuse SSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.
PMCID: PMC3711466  PMID: 19333948
8.  Work Productivity in Scleroderma – Analysis from the UCLA Scleroderma Quality of Life Study 
Arthritis care & research  2012;64(2):176-183.
To examine the productivity of patients with scleroderma (SSc) both outside and within the home in a large observational cohort.
162 patients completed the Work Productivity Survey. Patients indicated whether or not they were employed outside of the home, how many days/month they missed work (employment or household work) due to SSc and how many days/month productivity was decreased ≥ 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, HAQ-DI, FACIT-Fatigue, and Center of Epidemiologic Studies Depression Scale – Short Form (CESD).
The average age of patients was 51.8 years and 51% had limited SSc. Of 37% patients employed outside of the home, patients reported missing 2.6 days/month of work and had 2.5 days per month 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/month and had productivity reduced by average of 6 days/month. In the regression models, patients with lower education and poor assessment of overall health by physician were more likely to miss work outside the home. Patients with limited SSc and high HAQ-DI were more likely to miss work at home.
SSc has a major impact on productivity at home and at work. Nearly 40% of patients reported disability due to their SSc.
PMCID: PMC3266976  PMID: 22012885
Scleroderma; systemic sclerosis; work productivity survey; work productivity; word disability; epidemiology; FACIT-Fatigue; CESD; CESD-10; HAQ-DI
9.  Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus 
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.
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).
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%).
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.
PMCID: PMC3672798  PMID: 23343383
10.  Feasibility and Construct Validity of PROMIS and Legacy Instruments in an Academic Scleroderma Clinic—Analysis from the UCLA Scleroderma Quality of Life Study 
The NIH 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. For adults, 11 domains have been developed in physical, mental, and social health.
The objective of the current study was to assess feasibility and construct validity of PROMIS item banks versus legacy measures in a observational study in systemic sclerosis (SSc).
Patients with SSc in a single academic center completed computerized adaptive technology (CAT) administered PROMIS item banks during the clinic visit and legacy domains (using paper-and-pencil). The construct validity of PROMIS items was evaluated by examining correlations with corresponding legacy measures using multitrait-multimethod analysis.
Participants consisted of 143 SSc patients with an average age of 51.5 years; 71% were female and 68% were Caucasian. 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 .61 to .82).
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
PMCID: PMC3457915  PMID: 22264980
Systemic sclerosis; PROMIS; health-related quality of life; construct validity
11.  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 
Clinical immunology (Orlando, Fla.)  2011;141(3):293-303.
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 one 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.
PMCID: PMC3221795  PMID: 22015344
IL-4; T cells; imatinib; scleroderma; fibrosis
12.  Open-Label Pilot Trial of Imatinib Mesylate (Gleevec) in the Treatment of Systemic Sclerosis- Associated Active Interstitial Lung Disease (SSc-ILD) 
Arthritis and rheumatism  2011;63(11):3540-3546.
Transforming growth factor-beta (TGF-b) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis- interstitial lung disease (SSc-ILD) and imatinib is a potent inhibitor of TGF-b and PDGF production. We report a phase I/IIa open-label pilot study of imatinib in patients with SSc-ILD. Our primary aim was to assess imatinib’s safety; we also explored efficacy.
We recruited 20 SSc patients with FVC< 85% predicted, dyspnea on exertion, and presence of ground glass appearance on HRCT. Patients received oral imatinib therapy (up to 600 mg/day) for a period of 1 year. Adverse events, pulmonary function tests, and modified Rodnan skin score (MRSS) were captured every 3 months. The course of lung function, HAQ-DI and MRSS were modeled over the length of study to explore efficacy.
The majority of patients were female (65%), Caucasian (75%) and had diffuse SSc (70%). The baseline mean (SD) FVC%predicted was 65.2 (14.0) and MRSS was 18.7 (10.1). Mean(SD) imatinib dose was 445 (125) mg/day. Of 20 patients, 12 completed the study, 7 discontinued due to adverse events (AEs), and 1 patient was lost to follow-up. 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 towards an improvement of FVC%predicted of 1.74% (p>0.05) and MRSS of 3.9 units (p< 0.001).
Use of high-dose daily (600 mg/day) imatinib in SSc-ILD was associated with a large number of AEs. Our AE experience suggests that doses lower than 600 mg/day imatinib may be appropriate and that further dose ranging is needed to understand the therapeutic index of imatinib in SSc.
PMCID: PMC3205223  PMID: 21769849
imatinib; clinical trial; systemic sclerosis; scleroderma-related lung fibrosis
13.  Minimally Important Differences of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 
The Journal of Rheumatology  2011;38(9):1920-1924.
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.
We administered the UCLA SCTC GIT 2.0 to 115 patients with SSc at 2 time points 6 months apart. UCLA SCTC GIT 2.0 has 7 multi-item scales: Reflux, Distention/Bloating, Diarrhea, Fecal Soilage, Constipation, Emotional Well-being, and Social Functioning and a Total GIT score. All scales are scored from 0 (better HRQOL) to 3 (worse HRQOL) except the diarrhea and constipation scales (ranges are 0–2 and 0– 2.5, respectively). Patients also rated their overall, upper, and lower GIT involvement during the 2nd visit using a “Much better, somewhat better, almost the same, somewhat worse, or much worse” response scale. The minimally changed group was defined by those reporting they were somewhat better or somewhat worse compared to 1st visit.
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 Emotional Well-Being scale. For worsening, the MID estimates ranged from 0.06 for Fecal Soilage scale to 0.21 for the Social Functioning Scale.
We provide MID estimates for the UCLA SCTC GIT 2.0 scales. This information can aid in interpreting scale scores in future RCTs and observational studies.
PMCID: PMC3368014  PMID: 21724699
gastrointestinal; scleroderma; systemic sclerosis; UCLA SCTC GIT 2.0; minimally important differences; minimal clinically important differences
14.  Prevalence and correlates of sleep disturbance in systemic sclerosis—results from the UCLA scleroderma quality of life study 
Rheumatology (Oxford, England)  2011;50(7):1280-1287.
Objective. Rheumatologic disorders are associated with sleep disturbances. This study examines sleep disturbance correlates in patients with SSc.
Methods. Participants are 180 SSc patients in an observational study. At baseline, patients completed the Medical Outcomes Study Sleep measure (MOS-Sleep scale). In addition, patients were administered other patient-reported outcome (PRO) measures including the 36-item short form (SF-36), HAQ disability index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Center for Epidemiologic Studies Depression (CESD) scale and a University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Questionnaire (UCLA SCTC GIT 2.0). Descriptive statistics were assessed for six scales of MOS-Sleep and the 9-item sleep problem index (SLP-9; a composite index). We computed Spearman’s rank-order correlations between the MOS-Sleep scales and the HAQ-DI, FACIT-Fatigue, CESD, SSc-SCTC GIT 2.0 and SF-36 scales. In addition, we developed a regression model to assess predictors of SLP-9 scores. Covariates included demographics, physician variables of disease severity and patient-reported variables of worsening symptoms and the PRO measures.
Results. SSc patients reported a mean (s.d.) of 7.1 (1.73) h of sleep a night. Patients reported worse scores on four of six scales (except for snoring and sleep quantity) compared with the US general population (P < 0.001). SLP-9 was correlated with worsening pain and dyspnoea over the past 1 month, reflux scale of the UCLA SCTC GIT 2.0, CESD and FACIT-Fatigue (ρ 0.26–0.56). In the stepwise multivariate regression model, the CESD, worsening dyspnoea and reflux scale were significantly associated with SLP-9 index.
Conclusion. Sleep disturbances are common in SSc and are associated with worsening dyspnoea, depressed mood and severity of reflux symptoms.
PMCID: PMC3116211  PMID: 21324979
Systemic sclerosis; Scleroderma; Sleep; Depression; Gastroesophageal reflux; Quality of life; SF-36; HAQ disability index (HAQ-DI); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue); Center for Epidemiologic Studies Depression (CESD) scale; University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Questionnaire (UCLA SCTC GIT 2.0)
15.  Atherosclerosis in Systemic Sclerosis- A Systematic Review and Meta Analysis 
Arthritis and rheumatism  2011;63(7):2078-2090.
Systemic sclerosis (SSc) is characterized by calcification, vasculopathy, and endothelial wall damage, all of which can increase the risk for atherosclerosis and cardiovascular disease. Our objective was to perform a systematic review and meta-analysis to determine if atherosclerosis is increased in patients with SSc compared to healthy individuals.
We performed a systematic search of studies published in PubMed and the Cochrane database up to May 2010, and reviewed recently-published abstracts. Two reviewers independently screened articles to identify studies comparing rates of atherosclerosis in SSc patients vs. healthy controls using one of the following modalities: angiography, doppler ultrasound to assess plaque and carotid intima-medial thickness (CIMT), computer tomography, magnetic resonance imaging, flow mediated dilation (FMD), ankle-brachial index, or autopsy findings. For CIMT and FMD, we computed a pooled estimate of the summary mean difference (MD) and explored predictors of CIMT using random-effects meta-regression.
Of 3,156 articles initially identified, 33 were selected for the systematic review. Meta-analysis included 14 CIMT and 7 FMD studies. Compared to healthy controls, SSc patients had higher prevalence of coronary atherosclerosis, peripheral vascular disease, and cerebrovascular calcification. Meta-analysis showed SSc subjects had increased CIMT [MD 0.11mm (95% CI 0.05, 0.17), P=0.0006] and lower FMD [MD -3.07% (95%CI -5.44, -0.69), P=0.01]. There was marked heterogeneity between the studies, namely from variations in disease duration and difference in mean/median age between SSc and control groups.
Patients with SSc have increased atherosclerosis compared to healthy controls. Further studies should elucidate the mechanism of this increased risk.
PMCID: PMC3128188  PMID: 21480189
16.  Long-term therapy for chronic gout results in clinically important improvements in the health-related quality of life: short form-36 is responsive to change in chronic gout 
Rheumatology (Oxford, England)  2010;50(4):740-745.
Objective. Short Form-36 (SF-36) is a validated outcome measure to assess health-related quality of life (HRQOL) in patients with gout. We assessed responsiveness to change of SF-36 in patients with gout.
Methods. SF-36 was administered at baseline and at yearly intervals. We assessed the minimal clinically important differences (MCIDs) at the first and second year. We also assessed the responsiveness to change (effect size) and interpreted it based on Cohen’s criteria. We modelled the improvement (defined as ≥MCID) in SF-36 scales and summary scores. Covariates included age, presence of tophi, comorbidities, baseline joint involvement, baseline serum urate, change in serum urate and the number of flares from baseline to 12 months.
Results. Of 99 subjects, 96 were male, mean age was 57.1 years, disease duration was 8.2 years and 40.4% had tophi. Ninety-two patients were treated with urate-lowering therapy (ULT) and daily colchicine, and seven were only on colchicine. Baseline mean serum urate level was 8.9 mg/dl and mean number of flares was 4.7 over last year. ULTs were associated with reduction in serum uric acid and number of flares (P < 0.001 for both) over 12 months. Therapy was associated with 22–70% of the patients achieving MCID in SF-36 scores at 12 months. Effect size estimates ranged from negligible to large (SF-36 mental component summary 0.08–bodily pain 1.09). Reduction in flares independently predicted improvements in three SF-36 physical scales (P = 0.001–0.06). Improvement in SF-36 scores was maintained at 2 years.
Conclusion. In our real-life observational cohort, chronic urate lowering therapy and colchicine was associated with clinically meaningful improvements in HRQOL at 1 year and then maintained at 2 years. SF-36, especially physical domains and physical component summary, are responsive to change in gout.
PMCID: PMC3060621  PMID: 21147824
Gout; Health-related quality of life; Quality of life; Flares; Urate-lowering therapy; Minimal clinically important differences; Minimally important differences; Short Form-36, Gout prophylaxis
17.  Association of gastrointestinal involvement and depressive symptoms in patients with systemic sclerosis 
Rheumatology (Oxford, England)  2010;50(2):330-334.
Objectives. SSc-associated gastrointestinal tract involvement (SSc-GIT) is an important predictor of depressive symptoms. University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) is a 34-item valid instrument that captures GIT symptom severity and impact on quality of life. It has seven GI-specific scales and a total GIT score. The objectives were to assess: (i) whether there is an association between depressed mood with GI symptom scales as assessed by the UCLA SCTC GIT 2.0 instrument; and (ii) to explore which GI-specific symptom scales are associated with depressed mood in patients with SSc.
Methods. One hundred and fifty-two patients with SSc completed the UCLA SCTC GIT 2.0 and the Center for Epidemiologic Studies Short Depression scale (CES-D10). Patients were divided into depressed (CES-D ≥ 10) or non-depressed group (CES-D < 10) and compared using t-test or chi-square test. Multiple linear regression was used to determine associations between GI scales and depressed mood (CES-D).
Results. Study participants were 84% female, 78% Caucasian and 40% had depressed mood (CES-D10 ≥ 10). Patients with depressed mood had statistically worse GI scale scores (except fecal soilage) and worse total GIT score (P < 0.05). In the multivariable model reflux and constipation scales were independently associated with worse CES-D scores (P = 0.01–0.06)
Conclusion. SSc-GIT involvement is associated with depressed mood. Reflux and constipation scales of UCLA-SCTC GIT 2.0 were independently associated with CES-D. Future studies should assess if treatment of GIT symptoms will improve depressed mood in patients with SSc-GIT.
PMCID: PMC3021949  PMID: 20884655
Scleroderma; Systemic sclerosis; Depression; Center for Epidemiologic Studies Short Depression scale; Gastrointestinal involvement; Reflux; Constipation; University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0
18.  Gender and ethnicity differences in patients with diffuse systemic sclerosis—analysis from three large randomized clinical trials 
Rheumatology (Oxford, England)  2010;50(2):335-342.
Objective. Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs).
Method. Data from RCTs (n = 495) were pooled and analysed. Baseline characteristics were compared in men vs women and among ethnic groups. A linear mixed effects model was used to assess the predictors of MRSS, HAQ-DI and FVC%. The primary independent variables were time-in-study and its interaction with gender and ethnicity. The models were adjusted for other covariates that were significant at baseline between gender and ethnicity analyses.
Results. Men had lower HAQI-DI scores compared with women (P < 0.05). Among the three ethnic groups, Caucasians were older, African-Americans had lower FVC% predicted and Hispanics had greater tender joint counts (P < 0.05). The course of MRSS, HAQ-DI and FVC% predicted during the study period was not significantly different between gender and three ethnicities. Time-in-study was an independent predictor of improvement in MRSS and HAQ-DI.
Conclusion. Our analysis explores the influence of gender and ethnicity on disease course in RCTs. These findings are relevant to issues of future trial design.
PMCID: PMC3107588  PMID: 20889574
Scleroderma; Randomized clinical trial; Clinical trials; Systemic sclerosis; Gender; Race; Ethnicity; Diffuse cutaneous systemic sclerosis
19.  Course of Dermal Ulcers and Musculoskeletal Involvement in Systemic Sclerosis Patients in the Scleroderma Lung Study 
Arthritis care & research  2010;62(12):1772-1778.
To evaluate changes in vascular and musculoskeletal involvement in subjects in the Scleroderma Lung Study (SLS), a multicenter, double-blind, randomized, controlled trial comparing placebo treatment to oral cyclophosphamide for 1 year in systemic sclerosis (SSc) patients with interstitial lung disease. Subjects were then followed off study agent for an additional 12 months.
The following parameters were noted at baseline and every 6 months for each patient: digital tip ulcers, other dermal ulcers, joint swelling, joint tenderness, large joint contractures, muscle tenderness, muscle weakness, oral aperture, hand extension, and fist closure.
158 patients were enrolled from 13 centers in the United States; 79 were randomized to the cyclophosphamide group (CYC) and 79 to the placebo group. There were no differences in dermal ulcer and musculoskeletal measures between CYC and placebo groups at baseline, 12, and 24 months. Improvement in FVC % predicted was associated with improvement in Rodnan skin score (P<0.05) at 12 and 24 months, and with increased mean oral aperature at 24 months (P=0.005).
These data document the frequency and course of these vascular and musculoskeletal features over time, thus providing essential information for sample size calculations and magnitude of effect in future clinical trials. There was no treatment effect of cyclophosphamide on the vascular and musculoskeletal features described.
PMCID: PMC2994974  PMID: 20740615
Scleroderma; musculoskeletal; joints; vascular; randomized controlled trial; cyclophosphamide
20.  Disease Progression and Treatment Responses in a Prospective DMARD-naïve Seropositive Early Rheumatoid Arthritis Cohort: Does Gender Matter? 
The Journal of rheumatology  2010;37(12):2475-2485.
To assess gender differences in disease characteristics and treatment responses over time in a DMARD-naïve seropositive early rheumatoid arthritis (RA) cohort.
DMARD-naïve, seropositive early RA (<14 months) patients with polyarticular disease were recruited by the Western Consortium of Practicing Rheumatologists. Each patient was examined at study entry, after 6 and 12 months, and yearly thereafter. Clinical and demographic data were collected. We investigated gender differences in baseline disease characteristics and treatment using Chi-square, Mann-Whitney and t tests. We used generalized estimating equations (GEE) models for repeated measures to examine whether the rate of change of specific disease outcomes during the first 2 years after DMARD initiation were significantly influenced by gender.
At baseline, men (n=67) and women (n=225) had similar disease activity and radiographic damage; men, however, had significantly worse erosion, while women had worse joint space narrowing. Despite similar treatment, women had worse disease progression over the 2-year follow up, as assessed by trends in DAS28ESR4, physician global scores and tender joint counts. In the GEE model, gender was significantly associated with the rate of change of DAS28ESR4 scores (p=0.009), though not being independently associated with disease activity. Self-reported measures (HAQ-DI, patient global scores, fatigue, pain) were worse among women at baseline and throughout the study period. Men were more likely to achieve remission.
At baseline, men and women had similar disease activity and joint damage. Responses to treatment over time were, however, better among men in this pre-biologic era; women had worse progression despite similar treatment.
PMCID: PMC2996473  PMID: 20889597
Rheumatoid arthritis; Gender; Treatment response
21.  Health-Related Quality of Life in Adults Reporting Arthritis: Analysis from the National Health Measurement Study 
Arthritis is the leading cause of disability in the United States. We assess the generic health-related quality-of-life (HRQOL) among a nationally representative sample of US adults with and without self-reported arthritis.
The NHMS, a cross-sectional survey of 3844 adults (35–89 years) administered EuroQol-5D (EQ-5D), Health Utilities Index Mark 2 (HUI2) and 3 (HUI3), SF-36v2™, Quality of Well-being Scale self-administered form (QWB-SA), and the Health and Activities Limitations index (HALex) to each respondent via a telephone interview. Weighted multiple linear regression was used to generate age-gender-arthritis stratified unadjusted HRQOL means and means adjusted for sociodemographic, socioeconomic covariates and co-morbidities by arthritis-age category.
The estimated population prevalence of self-reported arthritis was 31%. People with arthritis were more likely to be female, older, of lower socioeconomic status, and had more self-reported comorbidities than were those not reporting arthritis. Adults with arthritis had lower HRQOL on six different indexes compared to adults without arthritis, , with overall differences ranging from 0.03 (QWB-SA, age group 65–74), to 0.17 (HUI3, age group 35–44; all p-value < .05),.
Arthritis in adults is associated with poorer HRQOL. We provide age-related reference values for six generic HRQOL measures in people with arthritis.
PMCID: PMC3156343  PMID: 21298347
22.  Association of IRF5 polymorphisms with activation of the interferon α pathway 
Annals of the rheumatic diseases  2009;69(3):611-617.
The genetic association of interferon regulatory factor 5 (IRF5) with systemic lupus erythematosus (SLE) susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, a study was undertaken to examine whether such genetic variation predisposes to activation of the interferon α (IFNα) pathway.
Using a computer simulated approach, 14 single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFNα and IFN-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. IFN-inducible gene expression was assessed in LCLs from children with SLE in the presence and absence of IFNα stimulation.
The major alleles of IRF5 rs13242262 and rs2280714 were associated with increased IRF5 mRNA expression levels in the CEU, CHB+JPT and YRI samples. The minor allele of IRF5 rs10488631 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU (pc=0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of IFN-inducible genes in LCLs by IFNα.
SNPs of IRF5 in healthy individuals of a number of ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFNα and IFN-inducible chemokine expression. Identifying individuals genetically predisposed to increased IFN-inducible gene and chemokine expression may allow early detection of risk for SLE.
PMCID: PMC3135414  PMID: 19854706
23.  Tendon friction rubs in early diffuse systemic sclerosis: prevalence, characteristics and longitudinal changes in a randomized controlled trial 
Rheumatology (Oxford, England)  2010;49(5):955-959.
Objectives. To characterize the baseline tendon friction rubs (TFRs) in early dcSSc and to evaluate the association of change in TFR over 6 and 12 months with changes in modified Rodnan skin score (MRSS) and HAQ-Disability Index (HAQ-DI) over 12 and 24 months, respectively.
Methods. We analysed data from the d-Pen study, a 2-year study in early dcSSc (⩽18 months from first non-Raynaud’s symptom). TFR was scored as present/absent at seven anatomical sites at baseline and every 6 months thereafter. Multivariable linear regression models assessed associations between TFR and change in MRSS, and change in the HAQ-DI, over 12 and 24 months, respectively. Covariates included baseline TFR, change in the TFR over 6 and 12 months, age, sex, duration of SSc, MRSS, and tender joint count and swollen joint count (SJC).
Results. Forty-nine (37%) of 134 patients had TFR at baseline, 50% had resolution of their TFR, whereas 21% developed new TFRs. Patients with baseline TFRs were likely to be Caucasian (86 vs 58%) and had a higher HAQ-DI score (P = 0.008). In regression analyses, change in TFR (P = 0.04) and baseline MRSS (P = 0.03) predicted change in MRSS over a 12-month period (Model R2 = 0.14). For the HAQ-DI model, independent predictors were change in TFR at 6 months (P = 0.008) and baseline SJC (P = 0.04, Model R2 = 0.19). Results were similar for 24-month models.
Conclusions. We document the presence of TFR very early in the course of dcSSc. Changes in TFR over 6 and 12 months predict changes in MRSS and HAQ-DI over 12 and 24 months, respectively.
PMCID: PMC2909791  PMID: 20144926
Early scleroderma; Diffuse SSc; D-Penicillamine study; Tendon friction rubs; Scleroderma clinical trial
24.  Health-related quality of life in adults reporting arthritis: analysis from the National Health Measurement Study 
Quality of Life Research  2011;20(7):1131-1140.
Arthritis is the leading cause of disability in the United States. We assess the generic health-related quality-of-life (HRQOL) among a nationally representative sample of US adults with and without self-reported arthritis.
The NHMS, a cross-sectional survey of 3,844 adults (35–89 years) administered EuroQol-5D (EQ-5D), Health Utilities Index Mark 2 (HUI2) and 3 (HUI3), SF-36v2™, Quality of Well-being Scale self-administered form (QWB-SA), and the Health and Activities Limitations index (HALex) to each respondent via a telephone interview. Weighted multiple linear regression was used to generate age-gender-arthritis-stratified unadjusted HRQOL means and means adjusted for sociodemographic, socioeconomic covariates and comorbidities by arthritis–age category.
The estimated population prevalence of self-reported arthritis was 31%. People with arthritis were more likely to be woman, older, of lower socioeconomic status, and had more self-reported comorbidities than were those not reporting arthritis. Adults with arthritis had lower HRQOL on six different indexes compared with adults without arthritis, with overall differences ranging from 0.03 (QWB-SA, age-group 65–74) to 0.17 (HUI3, age-group 35–44; all P-value < .05).
Arthritis in adults is associated with poorer HRQOL. We provide age-related reference values for six generic HRQOL measures in people with arthritis.
PMCID: PMC3156343  PMID: 21298347
Health-Related Quality of Life; HRQOL; Arthritis; National Health Measurement Study; Self-reported arthritis; EQ-5D; SF-6D; HUI2; HUI3; HALex; QWB; QWB-SA
25.  Rapamycin versus Methotrexate in Early Diffuse Systemic Sclerosis: Results from a Randomized, Single-blind Pilot Study 
Arthritis and rheumatism  2009;60(12):3821-3830.
To assess the safety and efficacy of rapamycin (RAPA) in the treatment of diffuse systemic sclerosis (SSc)
Eighteen patients with ≤5 years of diffuse SSc were randomized to receive RAPA or methotrexate (MTX) in a single-blind, 48-week study. Abnormalities in clinical and laboratory parameters were compared between the two treatment groups. The potential efficacy of the study drugs was evaluated by comparing the baseline and 48-week assessments, including the modified Rodnan Skin score (mRSS) and the Health Assessment Questionnaire Disability Index.
Baseline patient characteristics were similar in both groups (N = 9 in each). One patient who never took the study drug in the RAPA group was excluded from analysis. Three patients in each group withdrew from the study: two were treatment-related (severe hypertriglyceridemia associated with RAPA; pancytopenia associated with MTX) and four were SSc-related. Hypertriglyceridemia was the most notable side-effect associated with RAPA, but it was generally well-tolerated and treatable. The incidence and severity of other adverse drug reactions were comparable between two groups. Within each group, the mRSS score showed a significant improvement from baseline (P < 0.05). In the RAPA group, the patient global assessment showed a significant improvement from baseline while forced vital capacity declined from baseline. The disease activity scores at 48 weeks and their changes from baseline were not significantly different between two groups.
RAPA has a reasonable safety profile in a select group of scleroderma patients. Larger trials are needed to assess its efficacy in early diffuse SSc.
PMCID: PMC2841149  PMID: 19950289

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