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.
Systemic sclerosis; quality indicator
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.
Pulmonary hypertension; Systemic sclerosis; Borderline; Pulmonary hemodynamics
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.
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.
Scleroderma; systemic sclerosis; work productivity survey; work productivity; word disability; epidemiology; FACIT-Fatigue; CESD; CESD-10; HAQ-DI
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.
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
Systemic sclerosis; PROMIS; health-related quality of life; construct validity
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.
IL-4; T cells; imatinib; scleroderma; fibrosis
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.
imatinib; clinical trial; systemic sclerosis; scleroderma-related lung fibrosis
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.
gastrointestinal; scleroderma; systemic sclerosis; UCLA SCTC GIT 2.0; minimally important differences; minimal clinically important differences
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.
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)
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.
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.
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
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.
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
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.
Scleroderma; Randomized clinical trial; Clinical trials; Systemic sclerosis; Gender; Race; Ethnicity; Diffuse cutaneous systemic sclerosis
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.
Scleroderma; musculoskeletal; joints; vascular; randomized controlled trial; cyclophosphamide
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.
Rheumatoid arthritis; Gender; Treatment response
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.
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.
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.
Early scleroderma; Diffuse SSc; D-Penicillamine study; Tendon friction rubs; Scleroderma clinical trial
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.
Health-Related Quality of Life; HRQOL; Arthritis; National Health Measurement Study; Self-reported arthritis; EQ-5D; SF-6D; HUI2; HUI3; HALex; QWB; QWB-SA
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.
The Raynaud’s Condition Score (RCS) is a validated outcome measure for Raynaud’s phenomenon (RP). Our objective was to assess the minimally important difference (MID) and Patient Acceptable Symptom State (PASS) for RCS in patients with RP.
Subjects and Methods
Patients with active RP (N=162) [mean RCS > 25 (0–100 VAS)] participated in a placebo-controlled, cross over randomized clinical trial (RCT). Data from the 2 treatment groups were combined for this analysis. We administered retrospective and prospective anchors during the RCT. MID groups were defined as the group who reported being somewhat better (anchor#1) and a 1-step change from “unbearable” to “very severe” etc. (anchor#2). We considered patients as achieving PASS if they rated their Raynaud’s condition as ‘very mild’ or ‘mild’ at the last study visit.
The mean age of participants was 48.9 years and the mean baseline RCS score was 46.4. The RCS change score for the MID improvement group ranged from − 13.9 to − 14.3 points and PASS estimate was 34.0 points.
The MID and PASS estimates for RCS are 14–15 points for improvement and 34 points, respectively on a 0–100 scale in a large RCT of patients with active RP. This information can aid in interpreting RCS in future RP trials.
Systemic sclerosis; Patient Acceptable Symptom State; minimally important differences; Rayanud’s phenomenon
To assess the course of modified Rodnan skin score (MRSS) in patients with diffuse cutaneous systemic sclerosis (dcSSc) with different baseline disease durations (defined from the date of onset of first non-Raynaud’s phenomenon symptom) in 3 large randomized controlled trials (RCT).
Data from RCTs were pooled and analyzed: high dose versus low dose D-Penicillamine (D-Pen), recombinant human relaxin vs. placebo (relaxin), and oral bovine type I collagen vs. placebo (collagen) studies. Patients were divided into 5 groups according to their disease durations at baseline. The linear mixed model for correlated data was used to model the two predictors of MRSS: Time (in months) and disease duration.
At entry, mean MRSS score was 21.0 units in the D-Pen, 27.3 units in the relaxin, and 26.1 units in the collagen studies. Time in study was a significant predictor of improvement of MRSS regardless of disease duration at baseline (P-value: < 0.0001). Patients with disease duration ≥ 2 years showed a greater rate of decline compared to patients with < 2 years (P-values: < 0.05). Similar results were obtained when disease duration was reclassified by including Raynaud’s phenomenon in the definition.
Our study confirms recent findings that patients entered in the clinical trials do not follow the same trend in natural history of skin thickening as seen in the dcSSc populations previously reported in early open longitudinal studies. These findings have important implications in study design where “prevention of worsening” is the main objective.
Natural history; scleroderma; systemic sclerosis; clinical trials; modified Rodnan skin score
New methodologies allow the scores for the Health Assessment Questionnaire-Disability Index (HAQ-DI) to be translated into preferences/ utility scores. We evaluated the construct validity of the HAQ-DI derived SF-6D score and assessed its responsiveness to change over 6- and 12-month follow-up periods in patients with early aggressive rheumatoid arthritis (RA).
Patients (N=277) participating in an RA observational study completed self-reported measures of symptoms and the HAQ-DI at baseline, 6 and 12 months. Total Sharp scores, C-reactive protein and erythrocyte sedimentation rate were assessed using clinical data. Construct validity was assessed by examining the association between SF-6D score and patient-reported and clinical measures using Spearman correlation coefficients. The responsiveness of SF-6D to change was assessed using patient and physician assessments of the disease as clinical anchors. The magnitude of responsiveness was calculated using SF-6D effect size (ES).
Mean SF-6D scores were 0.690, 0.720, and 0.723 at baseline, 6, and 12-month follow-up visits, respectively. Baseline patient-reported measures had moderate-to-high correlations with baseline SF-6D (r: 0.43 to 0.52); whereas clinical measures had negligible-to-low correlations with SF-6D (r: 0.001 to 0.32). ES was moderate for the groups that were deemed to have improved (ES: 0.63–0.75) but negligible-to-small for those who did not (ES: 0.13–0.46).
Our data supports the validity and responsiveness of the HAQ-DI derived SF-6D score in an early RA cohort. These results support the use of HAQ-DI derived SF-6D in RA cohorts and clinical trials lacking preference-based measures.
SF-6D; Health Assessment Questionnaire-Disability Index; health utility; preference-based measures; early rheumatoid arthritis; cost-effectiveness analysis
To refine the previously developed scleroderma gastrointestinal tract (SSC-GIT 1.0) instrument.
We administered the SSC-GIT 1.0 and SF-36 to 152 patients with SSc; 1 item was added to SSC-GIT 1.0 to assess rectal incontinence. In addition, subjects completed a rating of the severity of their GIT involvement (from very mild to very severe). Evaluation of psychometric properties included internal consistency reliability, test-retest reliability (1.1 week mean time interval), and multitrait scaling analysis.
Study participants were female (84%) and Caucasian (81%); 55% had diffuse SSc. Self-rated severity of GIT involvement ranged from no symptoms to very mild (39%), to mild (21%), to moderate (31%), to severe/ very severe (9%). Of an initial 53 items in SSC-GIT 1.0, 19 items were excluded, leaving a 34-item revised instrument (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 [UCLA SCTC 2.0]). Analyses supported 7 multi-item scales: reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, and social functioning. Test-retest reliability estimates were ≥ 0.68 and coefficient alphas ≥0.67. Participants who rated their GIT disease as mild had lower scores on a 0-3 scale on all 7 scales. Also symptom scales were able to discriminate subjects with corresponding clinical GIT diagnoses. Total GIT Score, developed by averaging 6 of 7 scales (excluding constipation), was reliable and provided greater discrimination between mild, moderate, and severe self-rated GIT involvement than individual scales.
This study provides support for the reliability and validity of the UCLA-SCTC GIT 2.0, an improvement over SSC-GIT 1.0 and supports a Total GIT Score in SSc-GIT.