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1.  Evaluation of test characteristics for outcome measures used in Raynaud's phenomenon clinical trials 
Arthritis care & research  2013;65(4):630-636.
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: 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.
Results
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.
Conclusions
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.
doi:10.1002/acr.21858
PMCID: PMC3529989  PMID: 22972592
Raynaud 's phenomenon; Composite Response Index; systemic sclerosis; primary Raynaud's phenomenon; secondary Raynaud's phenomenon
2.  New directions for patient-centred care in scleroderma: the Scleroderma Patient-centred Intervention Network (SPIN) 
Clinical and experimental rheumatology  2012;30(2 0 71):S23-S29.
Systemic sclerosis (SSc), or scleroderma, is a chronic multisystem autoimmune disorder characterised by thickening and fibrosis of the skin and by the involvement of internal organs such as the lungs, kidneys, gastrointestinal tract, and heart. Because there is no cure, feasibly-implemented and easily accessible evidence-based interventions to improve health-related quality of life (HRQoL) are needed. Due to a lack of evidence, however, specific recommendations have not been made regarding non-pharmacological interventions (e.g. behavioural/psychological, educational, physical/occupational therapy) to improve HRQoL in SSc. The Scleroderma Patient-centred Intervention Network (SPIN) was recently organised to address this gap. SPIN is comprised of patient representatives, clinicians, and researchers from Canada, the USA, and Europe. The goal of SPIN, as described in this article, is to develop, test, and disseminate a set of accessible interventions designed to complement standard care in order to improve HRQoL outcomes in SSc.
PMCID: PMC3925434  PMID: 22244687
scleroderma; psychosocial; health-related quality of life; patient-centred care
3.  Predicting Treatment Outcomes and Responder Subsets in Scleroderma-related Interstitial Lung Disease 
Arthritis and rheumatism  2011;63(9):2797-2808.
Objectives
To identify baseline characteristics of patients with Scleroderma-Related Interstitial Lung Disease (SSc-ILD) which predict the most favorable response to a 12-month treatment with oral cyclophosphamide (CYC).
Methods
Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in %-predicted Forced Vital Capacity (FVC) and the placebo-adjusted change in %-predicted FVC over time (the CYC treatment effect).
Results
Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo-adjusted improvement in %-predicted FVC of 2.11% at 12 months which increased to 4.16% when patients were followed for another 6 months (p=0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates on baseline high-resolution computerized tomography (HRCT), the modified Rodnan Skin Score (mRSS), and Mahler's Baseline Dyspnea Index (BDI) as independent correlates of treatment response. When patients were stratified based on whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or the presence of a mRSS of at least 23, a subgroup emerged with an average CYC treatment effect of 4.73% at 12 months and 9.81% at 18 months (p<0.001). Conversely, there was no treatment effect (−0.58%) in patients with less severe HRCT findings and a lower mRSS.
Conclusions
A retrospective analysis of the Scleroderma Lung Study identified the severity of reticular infiltrates on baseline HRCT and the baseline mRSS as patient features that might predict responsiveness to CYC therapy.
doi:10.1002/art.30438
PMCID: PMC3910296  PMID: 21547897
4.  Quality indicator set for systemic sclerosis 
Clinical and experimental rheumatology  2011;29(2 0 65):S33-S39.
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.
Conclusion
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
5.  Validity, Reliability, and Feasibility of Durometer Measurements of Scleroderma Skin Disease in a Multicenter Treatment Trial 
Arthritis and rheumatism  2008;59(5):10.1002/art.23564.
Objective
To determine the validity, reliability, and feasibility of durometer measurements of skin hardness as an outcome measure in clinical trials of scleroderma.
Methods
Skin hardness was measured during a multicenter treatment trial for scleroderma using handheld digital durometers with a continuous scale. Skin thickness was measured by modified Rodnan skin score (MRSS). Other outcome data collected included the Scleroderma Health Assessment Questionnaire. In a reliability exercise in advance of the trial, 9 investigators examined the same 5 scleroderma patients by MRSS and durometry.
Results
Forty-three patients with early diffuse cutaneous systemic sclerosis were studied at 11 international centers (mean age 49 years [range 24–76], median disease duration 6.4 months [range 0.3–23], and median baseline MRSS 22 [range 11–38]). The reliability of durometer measurements was excellent, with high interobserver intraclass correlation coefficients (ICCs) (0.82–0.92), and each result was greater than the corresponding skin site ICCs for MRSS (0.54–0.85). Baseline durometer scores correlated well with MRSS (r = 0.69, P < 0.0001), patient self-assessments of skin disease (r = 0.69, P < 0.0001), and Health Assessment Questionnaire (HAQ) disability scores (r = 0.34, P = 0.03). Change in durometer scores correlated with change in MRSS (r = 0.70, P < 0.0001), change in patient self-assessments of skin disease (r = 0.52, P = 0.003), and change in HAQ disability scores (r = 0.42, P = 0.017). The effect size was greater for durometry than for MRSS or patient self-assessment.
Conclusion
Durometer measurements of skin hardness in patients with scleroderma are reliable, simple, accurate, demonstrate good sensitivity to change compared with traditional skin scoring, and reflect patients' self-assessments of their disease. Durometer measurements are valid, objective, and scalable, and should be considered for use as a complementary outcome measure to skin scoring in clinical trials of scleroderma.
doi:10.1002/art.23564
PMCID: PMC3887555  PMID: 18438905
6.  Significance of Sex in Achieving Sustained Remission in the Consortium of Rheumatology Researchers of North America (CORRONA) Cohort of Rheumatoid Arthritis Patients 
Arthritis care & research  2012;64(12):1811-1818.
Objective
To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women.
Methods
RA patients enrolled in the CORRONA cohort between October 2001 and January 2010 were selected for the present analyses. Detailed clinical, demographic and drug utilization data were available at enrollment (baseline) and at subsequent follow up visits. We examined the influence of sex on CDAI remission (CDAI≤2.8) using sustained remission or point remission as the primary outcome measure in multivariate stepwise logistic regression models. We stratified the data by RA duration at baseline (≤2 years or >2 years) to investigate whether RA duration had differential effects on remission in men and women.
Results
A total of 10,299 RA patients (2,406 men and 7,893 women) were available for this study. In both early and established RA, women had more severe disease at baseline with worse disease acitivity measures, modified Health Assessment Questionnaire Disability Index, pain visual analog scale and depression. Women were also more likely to have been treated with DMARDs and anti-TNF therapy compared to men. In the regression models, maleness was associated with sustained remission in early RA (OR: 1.38, 95% CI: 1.07, 1.78, p=0.01), but not in established RA. However, for point remission, an inverse association was observed with maleness in established RA (OR: 0.65, 95% CI: 0.48, 0.87, p=0.005) and not in early RA.
Conclusion
Within the large, real-life CORRONA cohort of RA patients, men were more likely to achieve sustained remission compared to women in early RA, although not in established RA.
doi:10.1002/acr.21762
PMCID: PMC3604992  PMID: 22730408
9.  Differences in Presentation of Younger and Older Systemic Sclerosis Patients in Clinical Trials 
Clinical and experimental rheumatology  2010;28(5 0 62):S10-S14.
Objective
To compare the characteristics of younger and older subjects with diffuse cutaneous systemic sclerosis (SSc) entering clinical trials.
Methods
Subjects were participants in three randomized interventional trials which shared relative uniformity of demographics and disease characteristics. Only subjects with diffuse cutaneous systemic sclerosis were evaluated. To maximize possible differences, the lowest (age<38 years) and highest quartiles (age>53 years) were used and a total of 264 diffuse cutaneous SSc (dcSSc) subjects were identified. For the comparison between two age groups, generalized linear mixed or linear models with adjustment for population norms, demographics and medications were employed to assess differences attributable to subject age.
Results
After adjustment for population norms and study effects, differences in diastolic blood pressure, alkaline phosphatase, AST, and creatinine phosphokinase (CK) were found between the two age groups. After further adjustment for demographics, disease duration and medications, older SSc patients still had significantly higher alkaline phosphatase (11 U/L higher), and lower CK (76 U/L lower) than younger patients (p<0.003 for all). All other variables were not significantly different in the two age groups.
Conclusion
Clinical baseline differences exist between younger and older patients with SSc; however, after adjustment for population norms and potential confounders, including medications, only differences in alkaline phosphatase (only 11U/L) and CK (76 U/L) remain. Overall, older patients with SSc in clinical trials seem to be more similar to younger patients than was previously thought.
PMCID: PMC3741408  PMID: 21050539
Scleroderma; Systemic sclerosis; Age
10.  The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context 
BMJ Open  2013;3(8):e003563.
Introduction
Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN.
Methods and analysis
SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500–2000 patients from centres across the world within a period of 5 years (2013–2018). Eligible participants are persons ≥18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once interventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions.
Ethics and dissemination
The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc.
doi:10.1136/bmjopen-2013-003563
PMCID: PMC3740254  PMID: 23929922
Rheumatology; Statistics & Research Methods; Rehabilitation Medicine; Mental Health
11.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
Patients with boPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and presence of exercise mPAP ≥30mmHg.
doi:10.1136/annrheumdis-2011-200546
PMCID: PMC3398226  PMID: 22307943
Pulmonary hypertension; Systemic sclerosis; Borderline; Pulmonary hemodynamics
12.  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.
Background/Purpose
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/art.24380
PMCID: PMC3711466  PMID: 19333948
13.  IRF5 polymorphism predicts prognosis in patients with systemic sclerosis 
Annals of the Rheumatic Diseases  2012;71(7):1197-1202.
Objective
The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.
Methods
The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study.
Results
Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%.
Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant.
Conclusion
An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.
doi:10.1136/annrheumdis-2011-200901
PMCID: PMC3375372  PMID: 22440820
14.  Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial 
The Journal of rheumatology  2013;40(4):455-460.
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.
doi:10.3899/jrheum.121087
PMCID: PMC3652008  PMID: 23418384
GASTRIC ANTRAL VASCULAR ECTASIA; GAVE; SYSTEMIC SCLEROSIS VASCULOPATHY; ENDOSCOPY
15.  Items for developing revised classification criteria in systemic sclerosis: results of a consensus exercise with the ACR/EULAR working committee for classification criteria in systemic sclerosis 
Arthritis care & research  2012;64(3):351-357.
Background
Classification criteria for systemic sclerosis (SSc) are being updated.
Objective
To select a set of items potentially useful for the classification of SSc using consensus procedures including the Delphi and nominal group techniques (NGT).
Methods
Items were identified through two independent consensus exercises performed by the Scleroderma Clinical Trials Consortium (SCTC) and the EULAR Scleroderma Trials and Research Group (EUSTAR). The first-round items from both exercises were collated and redundancies were removed leaving 168 items. A 3-round Delphi exercise was performed using a 1–9 scale (1=completely inappropriate and 9=completely appropriate) and a consensus meeting using NGT. During the last Delphi, the items were ranked on a 1–10 scale.
Results
Round 1: 106 experts rated the 168 items. Those with a median score <4 were removed, resulting in a list of 102 items. Round 2: The items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n=16), resulting in 23 items. Round 3: SSc experts (n=26) then individually scored each of the 23 items in a last Delphi round, using an appropriateness score (1–9) and ranking their 10 most appropriate items for classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern and Raynaud’s phenomenon ranked highest in the final list that also included items indicating internal organ involvement.
Conclusion
The Delphi exercise and NGT resulted in a set of 23 items for classification of SSc which will be assessed for their discriminative properties in a prospective study.
doi:10.1002/acr.20679
PMCID: PMC3288452  PMID: 22052558
Delphi technique; nominal group technique; systemic sclerosis; scleroderma; classification; classification criteria
16.  Validation of potential classification criteria for systemic sclerosis 
Arthritis care & research  2012;64(3):358-367.
Background
Classification criteria for systemic sclerosis (SSc) are being updated jointly by ACR and EULAR. Potential items for classification were reduced to 23 using Delphi and Nominal Group Techniques. We evaluated the face, discriminant and construct validity of the items to be further studied as potential criteria.
Methods
Face validity was evaluated using the frequency of items in patients sampled from the Canadian Scleroderma Research Group, 1000 Faces of Lupus, the Pittsburgh, Toronto, Madrid and Berlin CTD databases. SSc (n=783) were compared to 1071 patients with diseases similar to SSc (mimickers): SLE (n=499), myositis (n=171), Sjögren’s syndrome (n=95), Raynaud’s phenomenon (RP) (n=228), MCTD (n=29), and idiopathic PAH (n=49). Discriminant validity was evaluated using odds ratios (OR). For construct validity, empiric ranking was compared to expert ranking.
Results
Compared to mimickers, SSc are more likely to have skin thickening (OR=427), telangiectasias (OR=91), anti-RNA polymerase III antibody (OR=75), puffy fingers (OR=35), finger flexion contractures (OR=29), tendon/bursal friction rubs (OR=27), anti-topoisomerase-I antibody (OR=25), RP (OR=24), finger tip ulcers/pitting scars (OR=19), anti-centromere antibody(OR=14), abnormal nailfold capillaries (OR=10), GERD symptoms (OR=8), and ANA, calcinosis, dysphagia, esophageal dilation (all OR=6), interstitial lung disease/pulmonary fibrosis (OR=5) and anti-PM-Scl antibody (OR=2). Reduced DLCO, PAH, and reduced FVC had OR<2. Renal crisis and digital pulp loss/acro-osteolysis did not occur in SSc mimickers (OR not estimated). Empiric and expert ranking were correlated (Spearman rho 0.53, p=0.01).
Conclusion
The candidate items have good face, discriminant and construct validity. Further item reduction will be evaluated in prospective SSc and mimicker cases.
doi:10.1002/acr.20684
PMCID: PMC3376721  PMID: 22052658
Systemic Sclerosis; Scleroderma; Classification Criteria; Validity; Bayesian
17.  Work Productivity in Scleroderma – Analysis from the UCLA Scleroderma Quality of Life Study 
Arthritis care & research  2012;64(2):176-183.
Objective
To examine the productivity of patients with scleroderma (SSc) both outside and within the home in a large observational cohort.
Methods
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).
Results
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.
Conclusion
SSc has a major impact on productivity at home and at work. Nearly 40% of patients reported disability due to their SSc.
doi:10.1002/acr.20676
PMCID: PMC3266976  PMID: 22012885
Scleroderma; systemic sclerosis; work productivity survey; work productivity; word disability; epidemiology; FACIT-Fatigue; CESD; CESD-10; HAQ-DI
18.  Feasibility and Construct Validity of PROMIS and Legacy Instruments in an Academic Scleroderma Clinic—Analysis from the UCLA Scleroderma Quality of Life Study 
Background
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.
Purpose
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).
Methods
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.
Results
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).
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
doi:10.1016/j.jval.2011.08.006
PMCID: PMC3457915  PMID: 22264980
Systemic sclerosis; PROMIS; health-related quality of life; construct validity
19.  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.
doi:10.1016/j.clim.2011.08.010
PMCID: PMC3221795  PMID: 22015344
IL-4; T cells; imatinib; scleroderma; fibrosis
21.  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.
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/art.30548
PMCID: PMC3205223  PMID: 21769849
imatinib; clinical trial; systemic sclerosis; scleroderma-related lung fibrosis
22.  Methods of Formal Consensus in Classification/Diagnostic Criteria and Guideline Development 
Guideline or diagnostic criteria in clinical practice assist physicians in their clinical decision-making and improve health outcomes for patients. Diagnostic and classification criteria are based on evidence from rigorously conducted controlled studies. Formal group consensus methods have been developed to organize subjective judgments and to synthesize them with the available evidence. This review discusses four types of formal consensus methods used in the health field and their applications in rheumatology: the Delphi method, nominal group technique, RAND/UCLA Appropriateness Method, and National Institutes of Health consensus development conference.
doi:10.1016/j.semarthrit.2010.12.001
PMCID: PMC3131416  PMID: 21420149
23.  Clinical Course of Lung Physiology in Patients with Scleroderma and Interstitial Lung Disease: Analysis of the Scleroderma Lung Study Placebo Group 
Arthritis and rheumatism  2011;63(10):3078-3085.
Background
Patients with scleroderma interstitial lung disease (SSc-ILD) are thought to have the greatest decline in lung function (forced vital capacity % predicted [FVC%]) in the early years after onset of systemic sclerosis (SSc). We assessed the natural history of FVC% decline in patients receiving placebo in the Scleroderma Lung Study and evaluated possible factors for cohort enrichment for future therapeutic trials.
Methods
Patients randomized to placebo (N=79) were divided into 3 groups based on SSc disease duration (0–2, 2–4 and >4 years). Descriptive statistics and a mixed effect model were used to analyze the rate of decline of FVC% over a 1-year period. We performed additional analyses stratified by severity of fibrosis on HRCT and explored interactions of severity and disease duration.
Results
The mean (SD) decline in the unadjusted FVC% during the 12-month period was 4.2 (12.8)%. At baseline, 28.5%, 43.0% and 28.5% of patients were in 0–2, 2–4 and >4 years disease groups, respectively. Rate of decline in FVC% was not significantly different across the 3 disease groups (P=0.85). When stratified by baseline fibrosis on HRCT, rate of decline of FVC% was statistically greater in the severe fibrosis group (annualized decline in FVC% in the severe group=7.2 vs. 2.7, p=0.008). The decline in the severe fibrosis group was most pronounced in those with relatively short disease duration (0–2 years, annualized decline= 7.0%).
Conclusion
Patients with SSc-ILD in the Scleroderma Lung Study had similar rates of progression of lung disease irrespective of disease duration. Baseline HRCT fibrosis score is a predictor of future FVC% decline in the absence of effective treatment.
doi:10.1002/art.30467
PMCID: PMC3183128  PMID: 21618205
24.  Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): Baseline Characteristics and Description of Study Population 
The Journal of rheumatology  2011;38(10):2172-2179.
Objective
Pulmonary arterial hypertension (PAH) increases mortality in systemic sclerosis (SSc). The multicenter PHAROS (Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma) registry prospectively follows SSc subjects at high-risk for, or with incident pulmonary hypertension (PH). Herein, we describe registry design and baseline characteristics of subjects enrolled during the first 18 months since study inception.
Methods
High-risk subjects are enrolled and classified as Pre-PAH if they have 1) carbon monoxide diffusing capacity (DLCO) < 55% predicted, 2) % predicted forced vital capacity/DLCO ratio ≥1.6, or 3) an estimated right ventricular systolic pressure > 35 mm Hg on echocardiography. Subjects with right heart catheterization confirmed incident PH (mean pulmonary artery pressure ≥ 25 mm Hg within previous 6 months) are subclassified into PAH, pulmonary venous hypertension secondary to left-sided heart disease (PVH), and PH due to interstitial lung disease (PH-ILD). Baseline and biannual demographic, clinical, and laboratory data as well as patient-reported health questionnaires are collected.
Results
There are 237 subjects enrolled in PHAROS. The majority are Caucasian (73%) and women (87%). There are 166 Pre-PAH and 71 Definite PH subjects (49 PAH, 7 PVH, and 15 PH-ILD).
Conclusion
PHAROS is the largest U.S. and Canadian cohort of SSc subjects at high-risk for or with incident PAH. PAH-specific therapies are approved for 49/71 subjects with RHC-confirmed-PAH. Analyses of PHAROS registry data will permit identification of risk factors for the development of PAH amongst SSc patients at high-risk for PAH and enhance our understanding of the course of SSc-PAH.
doi:10.3899/jrheum.101243
PMCID: PMC3230328  PMID: 21844142
Systemic scleroderma; Pulmonary hypertension; Registry; Pulmonary arterial hypertension
25.  Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: Results from a cross-sectional survey 
Background
The prevalence of gout is increasing, and most research on the associated burden has focused on serum urate (sUA) levels. The present study quantifies the impact of the presence of tophi and frequency of acute gout attacks on health-related quality of life (HRQOL), productivity, and healthcare resource utilization.
Methods
Patients with self-reported gout (n = 620; 338 in US and 282 across France, Germany, and UK) were contacted based on inclusion in the 2010 US and EU National Health and Wellness Surveys (Kantar Health) and the Lightspeed Research ailment panel. Respondents were categorized into mutually-exclusive groups based on number of gout flares experienced in the past 12 months (0/don’t recall, 1–2, 3, 4–5, 6+), current presence of tophi (none, 1+, or not sure), and sUA level awareness (yes, no). HRQOL (SF-12v2), healthcare provider visits in the last 6 months, and work productivity and activity impairment (WPAI) were compared across groups.
Results
Most patients were males, mean age of 61 years, who reported experiencing at least one acute gout flare in the past 12 months, and 12.3% (n = 76) reported presence of tophi. Among the 27.7% (n = 172) of patients who were aware of their sUA levels, higher sUA was associated with more flares and tophi. Decreased HRQOL was associated with more frequent flares and presence of tophi. In multivariable models predicting outcomes based on presence of tophi and number of flares, both flares (≥4) and tophi (≥1) were associated with HRQOL decrements on physical and mental component summary scores and health utilities (all p < 0.05), after adjustment for age, gender, and time since diagnosis. Flares were also associated with greater activity impairment.
Conclusions
Impairments associated with gout flares and presence of tophi, across patients in the US and EU, underscore the importance of effective management of this potentially curable condition.
doi:10.1186/1477-7525-10-117
PMCID: PMC3499162  PMID: 22999027
Gout; Quality of life; Productivity; Refractory chronic gout

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