Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis

INTRODUCTION: Efficacy and safety of lenabasum, a cannabinoid type 2-receptor agonist, was tested in a Phase 3 study in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multi-national double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments including immunosuppressive therapies (IST). RESULTS: The primary endpoint, ACR Combined Response Index in dcSSc (ACR-CRISS) score at Week 52, lenabasum 20 mg BID versus placebo, was not met, with ACR-CRISS scores of 0.888 versus 0.887, P = 0.4972, mixed models repeated measures (MMRM). Change in modified Rodnan Skin Score (mRSS) at Week 52 was -6.7 versus -8.1 points for lenabasum 20 mg BID versus placebo, P = 0.1183, MMRM. Pre-specified analyses showed higher ACR-CRISS scores, greater improvement in mRSS, and less decline in forced vital capacity in subjects on background mycophenolate and those receiving IST for ≤ 1 year duration. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSIONS: A benefit of lenabasum in dcSSc was not demonstrated. The majority of patients were treated with background IST, and treatment with MMF in particular was associated with better outcomes. This supports the use of IST in the treatment of dcSSc, and highlights the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as clinical care

Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations

All authors: Olga Y. Gorlova , Yafang Li, Ivan Gorlov, Jun Ying, Wei V. Chen, Shervin Assassi, John D. Reveille, Frank C. Arnett, Xiaodong Zhou, Lara Bossini-Castillo, Elena Lopez-Isac, Marialbert Acosta-Herrera, Peter K. Gregersen, Annette T. Lee, Virginia D. Steen, Barri J. Fessler, Dinesh Khanna, Elena Schiopu, Richard M. Silver, Jerry A. Molitor, Daniel E. Furst, Suzanne Kafaja, Robert W. Simms, Robert A. Lafyatis, Patricia Carreira, Carmen Pilar Simeon, Ivan Castellvi, Emma Beltran, Norberto Ortego, Christopher I. Amos, Javier Martin, Maureen D. Mayes.Data Availability Statement: Genetic data is available from dbGaP repository (https://www.ncbi. nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_ id=phs000357.v1.p1).Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.Funding was provided to MDM by the National Institutes of Health (NIH) the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS https://www.niams.nih.gov/) Centers of Research Translation (CORT) P50-AR054144, NIH grant N01-AR-02251 and R01-AR-055258, and the Department of Defense (DD) Congressionally Directed Medical Research Program (http://cdmrp.army.mil/) W81XWH-07-1-011 and WX81XWH-13-1-0452 for the collection, analysis and interpretation of the data

Validation of the Body Concealment Scale for Scleroderma (BCSS): Replication in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort

© 2016 Elsevier Ltd Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages

Ultrasound characterization of cutaneous ulcers in systemic sclerosis

Skin ulcers in scleroderma (SSc) patients are considered a major challenge, both in clinical assessment and treatment decisions. The objective of our study is to assess ultrasonographic (US) morphology of skin ulcers in SSc patients and evaluate if US will be of value in enhancing our clinical information and influence our management plans. We examined a convenience sample of 21 skin ulcers reported in 10 SSc patients by US. We used a previously published US definition of normal skin and developed a preliminary US definition of skin ulcer. Skin ulcers were evaluated by gray scale (GS) and power Doppler (PD) and separated into ulcer and non-ulcer lesions; pain and ulcer measures were obtained using visual analogue scales (VAS). Lesions were characterized and ulcers were clinically and sonographically measured. Ten patients presenting with 21 skin lesions were examined by US. Applying our US definition of skin ulcer, all ulcers were available to measure by ultrasound. Eight lesions were sonographically defined as ulcers, and 13 lesions as non-ulcer lesions. Three ulcers had high PD signals suggestive of infection requiring antibiotic treatment and were monitored for 2 weeks showing a decrease of the pain, VAS, and PD signals. Five lesions showed subclinical calcinosis. This is the first study to show the promising role of US in defining skin ulcers of SSc patients. US may support the assessment of morphology and extent of skin ulcers in SSc and can be a helpful tool for detecting underlying pathology.Egyptian governmen

Reliability, validity and responsiveness to change of the Saint George’s Respiratory Questionnaire in early diffuse cutaneous systemic sclerosis

ObjectiveDyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George's Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study.MethodsAt enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach's α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24-0.36 were considered moderate and >0.37 was considered large.ResultsA total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70-0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33-0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001-0.03). At follow-up, all scales were responsive to change using different anchors.ConclusionThe SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD

Evaluation of the Satisfaction with Appearance Scale and Its Short Form in Systemic Sclerosis: Analysis from the UCLA Scleroderma Quality of Life Study

ObjectiveChanges in appearance are common in patients with systemic sclerosis (SSc) and can significantly affect well-being. The Satisfaction with Appearance Scale (SWAP) measures body image dissatisfaction in persons with visible disfigurement; the Brief-Satisfaction with Appearance Scale (Brief-SWAP) is its short form. The present study evaluated the reliability and validity of SWAP and Brief-SWAP scores in SSc.MethodsA sample of 207 patients with SSc participating in the University of California, Los Angeles Scleroderma Quality of Life Study completed the SWAP. Brief-SWAP scores were derived from the SWAP. The structural validity of both measures was investigated using confirmatory factor analysis. Internal consistency reliability of total and subscale scores was assessed with Cronbach's alpha coefficients. Convergent and divergent validity was evaluated using the Center for Epidemiological Studies Depression Scale, the Health Assessment Questionnaire-Disability Index, and the Medical Outcomes Study Short Form-36 questionnaire.ResultsSWAP and Brief-SWAP total scores were highly correlated (r = 0.97). The 4-factor structure of the SWAP fit well descriptively; the 2-factor structure of the Brief-SWAP fit well descriptively and statistically. Internal consistencies for total and subscale scores were good, and results supported convergent and divergent validity.ConclusionBoth versions are suitable for use in patients with SSc. The Brief-SWAP is most efficient; the full SWAP yields additional subscales that may be informative in understanding body image issues in patients with SSc

Validation of Sonography findings of synovitis and tenosynovitis of hands and wrists in patients with systemic sclerosis

ObjectivesValidating musculoskeletal ultrasound features of the joints and tendons of the hands in a large scleroderma cohort.MethodsA total of 81 scleroderma patients participated in this prospective, cross-sectional study. Grayscale and power Doppler musculoskeletal ultrasound images of 13 joints and 5 tendons of the wrist and hand were obtained. Clinical assessment included modified Rodnan skin thickness score, joint count, and Scleroderma Health Assessment Questionnaire. Face validity, content validity, construct validity, and feasibility were assessed.ResultsMean age was 53.8 years (range 22-80), 76.5% were females, and disease duration ranged from 0.25 to 29 years. Mean length of the examination was 36 min. Scleroderma Health Assessment Questionnaire-Disability Index correlated with musculoskeletal ultrasound erosions (r = 0.5, p = 0.0003). Skin score correlated with tendinitis grayscale (r = 0.26, p = 0.02). Intra-reader correlation coefficient for musculoskeletal ultrasound was 0.96 for the joints and could not be calculated for tendons because there were too few positive findings. When tendon changes existed, percent of agreement was 77.7%-83.3%.ConclusionMusculoskeletal ultrasound of 13 joints and 5 tendons of the hands and wrist has face and content validity. Construct validity was shown for the tendons and erosion scores. Feasibility and reliability were partially validated

Reliability and minimal clinically important differences of forced vital capacity: Results from the Scleroderma Lung Studies (SLS-I and SLS-II).

ObjectivesTo assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II.MethodsUsing data from SLS I and II (N=300), we evaluated the test-retest reliability for FVC% predicted (FVC%; screening vs. baseline) using intra-class correlation (ICC). MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and II) using 2 anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the SF-36 Health Transition question: "Compared to one year ago, how would you rate your health in general now?", where "somewhat better" or "somewhat worse" were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total ILD (QILD) on HRCT.ResultsReliability of FVC%, assessed at a mean of 34 days, was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0 % to 5.3% and for worsening from -3.0% to -3.3%. FVC% improvement by ≥MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, while FVC% worsening ≥MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF.ConclusionFVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in SSc-ILD based changes at 12 months from baseline in two clinical trials. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT00004563 and NCT00883129