Disease Features and Gastrointestinal Microbial Composition in Patients with Systemic Sclerosis from Two Independent Cohorts.

OBJECTIVE: The study objective was to examine alterations in gastrointestinal (GI) microbial composition in patients with systemic sclerosis (SSc) and to investigate the relationship between SSc features and GI microbiota using two independent, international cohorts. METHODS: Prospective patients with SSc from Lund University (LU), Sweden, from the University of California, Los Angeles (UCLA), United States, and control subjects provided stool specimens for 16S ribosomal RNA sequencing. Alpha and beta diversity analyses were performed. Multivariate negative binomial models identified differentially abundant genera between groups. RESULTS: Patients from LU with SSc (n = 106) with recent SSc diagnosis (median disease duration 2.0 years) had lower abundance of commensal genera (eg, Faecalibacterium) and higher abundance of pathobiont genera (eg, Desulfovibrio) than LU-controls (n = 85). Patients from UCLA with SSc (n = 71) had a similar prevalence of females, a similar body mass index, and similar age but an increased disease duration (median 7.1 years) compared with patients from LU with SSc. Factors associated with beta diversity in patients with SSc from both LU and UCLA included disease duration (P = 0.0016), interstitial lung disease (P = 0.003), small intestinal bacterial overgrowth (P = 0.002), and immunosuppression use (P = 0.014). In multivariable analysis, the UCLA-SSc cohort had higher abundance of specific pathobiont genera (eg, Streptococcus) compared with the LU-SSc cohort. CONCLUSION: Enrichments and depletions in certain microbial genera were observed in patients recently diagnosed with SSc, suggesting that dysbiosis is present in early SSc. Specific disease features were independently associated with fecal microbial composition in both cohorts. After controlling for these factors, the abundance of several pathobiont bacteria differed between the cohorts, suggesting that environmental factors, along with disease manifestations, should be considered in future SSc studies.

Predictive Significance of Serum Interferon-Inducible Protein Score for Response to Treatment in Systemic Sclerosis-Related Interstitial Lung Disease.

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, ß2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3ß) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. RESULTS: Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). CONCLUSION: A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC.

Racial Disparities in Systemic Sclerosis: Short- and Long-Term Outcomes Among African American Participants of SLS I and II.

OBJECTIVE: To evaluate short- and long-term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomized 158 participants with systemic sclerosis-interstitial lung disease (SSc-ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc-ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). Joint models compared the course of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) between AA and non-AA, and Cox proportional hazard models assessed long-term morbidity and mortality outcomes. RESULTS: In SLS I, there was no difference in the course of the FVC or DLCO between AA and non-AA in either treatment arm. In SLS II, AA had an improved course of the FVC compared with non-AA in the CYC arm; in the MMF arm, there was no difference in FVC course. There was no difference in DLCO course in either arm. Time to death and respiratory failure were similar for AA and non-AA in SLS I. There was a trend for improved survival and time to respiratory failure in AA compared with non-AA in SLS II. AA race was not independently associated with mortality in the SLS I or II in the Cox models. CONCLUSION: Data from two randomized controlled trials demonstrated that AA patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-AA patients. These findings contrast with the racial disparities described in prior observational studies and warrant further investigation.

The MUC5B promoter variant does not predict progression of interstitial lung disease in systemic sclerosis.

OBJECTIVE: To investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF). METHODS: SSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism. Joint models were created to examine how the presence of this variant affected the course of the forced vital capacity (FVC) over 2 years. Linear regression models were used to investigate the relationship between the presence of this variant and the change in quantitative radiographic fibrosis. RESULTS: Among 128 participants who were tested for this variant, 18% possessed at least one copy of the MUC5B minor allele. Patients with at least one copy of this allele were similar to those without the allele with respect to age, sex, SSc subtype, ILD disease severity; however, this variant was rare among African Americans (3.7%). The presence of the MUC5B variant did not affect the course of the FVC, nor the change in quantitative radiographic fibrosis, ground glass or ILD scores in either treatment arm. CONCLUSION: In the context of a randomized controlled trial for SSc-ILD, the presence of the MUC5B variant did not predict disease severity, nor affect treatment response to MMF or CYC. Future studies are needed to determine whether this variant affects ILD progression in other SSc cohorts and in patients receiving anti-fibrotic therapy.

Treatment With Mycophenolate and Cyclophosphamide Leads to Clinically Meaningful Improvements in Patient-Reported Outcomes in Scleroderma Lung Disease: Results of Scleroderma Lung Study II.

OBJECTIVE: Our objective was to determine if treatment with cyclophosphamide (CYC) and mycophenolate mofetil (MMF) improves patient-reported outcomes (PROs) among patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: This study examined PROs in patients with SSc-ILD (N = 142) who participated in the Scleroderma Lung Study II, a randomized controlled trial comparing MMF for 2 years with oral CYC for 1 year followed by 1 year of a placebo. Joint models were created to evaluate the course of PROs over 2 years. The difference in PRO scores from baseline to 24 months was measured, and the percentage of patients meeting the minimum clinically important difference (MCID) was calculated. Correlations between PROs and SSc-ILD disease severity measures were also examined. RESULTS: Treatment with CYC and MMF led to improvements in several PROs with no between-treatment differences. Scores for the Transitional Dyspnea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) improved significantly over 2 years, and 29%/24% and 28%/25% of participants in the CYC/MMF groups met or exceeded the MCID estimates for TDI and SGRQ, respectively. At baseline, the forced vital capacity (FVC) percentage predicted (FVC%-predicted) did not correlate with the Baseline Dyspnea Index or SGRQ. However, improvements in the FVC%-predicted were weakly associated with improvements in dyspnea (assessed by the TDI) and SGRQ scores. CONCLUSION: Treatment with CYC and MMF improved overall health-related quality of life in patients with SSc-ILD. The relationship between PRO measures and the FVC was relatively weak, suggesting that PROs provide complementary information about treatment efficacy not captured by changes in the FVC alone in this patient population.

Longitudinal Characterisation of the Gastrointestinal Tract Microbiome in Systemic Sclerosis.

Objectives: To evaluate changes in microbial composition and the evolution of gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc). Methods: Adult SSc patients provided stool specimens every 3 months over the course of 1 year. Participants completed the University of California, Los Angeles (UCLA) GIT 2.0 questionnaire to assess GIT symptom severity at each stool collection. The microbiota from these samples were determined by Illumina HiSeq 2500 16S ribosomal RNA sequencing (Illumina, Inc., San Diego, California, USA). Mixed effect models evaluated changes in GIT symptoms and microbial composition over time. Results: Among 19 patients with SSc (female; 89.5%; median age: 51.3 years), the median disease duration was 7 years and the baseline total GIT 2.0 score was 0.7 (standard deviation: 0.6). The majority of participants (63%) provided at least four stool samples over the course of the 12-month study. Patients with longer disease durations had increased GIT symptoms over the course of the study. There was no difference in the course of GIT symptoms over time between patients with limited versus diffuse cutaneous disease. The relative abundances of specific genera did not change over time within individual subjects. After controlling for age, sex, ethnicity, disease duration, and SSc subtype (i.e., limited versus diffuse), low abundance of Bacteroides was associated with increased GIT symptoms over time. Conclusion: This study is the first to have longitudinally characterised the lower GIT microbiome in SSc patients and demonstrated relative stability of genera abundance over the course of 1 year. The findings provide additional evidence that specific genera are associated with SSc-GIT symptoms and warrant further evaluation in larger SSc studies.

Validity and correlates of the Brief Satisfaction With Appearance Scale for patients with limited and diffuse systemic sclerosis: Analysis from the University of California, Los Angeles Scleroderma Quality of Life Study.

Objective: The Brief Satisfaction With Appearance Scale measures two dimensions (Dissatisfaction with Appearance and Social Discomfort) of body image dissatisfaction in systemic sclerosis. This study examined the structural validity of the Brief Satisfaction With Appearance Scale across limited and diffuse systemic sclerosis subtypes, compared body image dissatisfaction by systemic sclerosis subtype, and identified the significant sociodemographic and medical correlates of body image dissatisfaction and whether they differed by subtype. Methods: Participants were 183 adults participating in the University of California, Los Angeles Scleroderma Quality of Life Study with limited cutaneous (n = 101) or diffuse cutaneous (n = 82) systemic sclerosis who received clinical examinations and completed questionnaires. Multiple-group confirmatory factor analysis, multivariate analysis of variance, and structural equation modeling were used. Results: The Brief Satisfaction With Appearance Scale's two-factor structure fit well for both subtypes. Patients with diffuse systemic sclerosis reported greater body image dissatisfaction on both factors than patients with limited disease. Greater Dissatisfaction with Appearance was associated with younger age and being unmarried for limited patients, and with younger age and increased finger/hand skin involvement for diffuse patients. Greater Social Discomfort was associated with younger age and being unmarried for both subtypes. Conclusion: The Brief Satisfaction With Appearance Scale scores can be meaningfully compared across limited and diffuse systemic sclerosis. Patients with diffuse disease reported more body image dissatisfaction than those with limited disease. Findings demonstrate that both medical and sociodemographic variables are associated with body image dissatisfaction in systemic sclerosis and can be used to identify which patients may be at increased risk for body image dissatisfaction.

Coping profiles and health outcomes among individuals with systemic sclerosis: A latent profile analysis approach.

Background: Systemic sclerosis has negative implications for quality of life, and coping is a mechanism by which individuals can adapt more successfully to illness. This study (1) identified coping profiles in patients with systemic sclerosis and (2) examined distress and disability correlates of the profiles. Methods: A sample of 93 patients with confirmed diagnoses of systemic sclerosis received clinical examinations and reported on coping, psychological distress, and health-related disability. Latent profile analysis was used to identify coping-based profile groups. The profile groups were then compared on psychological distress and health-related disability, controlling for disease severity. Results: A two-profile solution was supported: Active Copers emphasized problem-focused, social support, counting blessings, and religious approaches to coping with systemic sclerosis. Passive Copers emphasized blaming self and others, avoidance, and wishful thinking approaches to coping. Active Copers reported significantly less psychological distress than Passive Copers, but no significant differences were found for health-related disability. Discussion: The findings identify multidimensional patterns of coping that are differentially related to psychological distress in systemic sclerosis patients. These findings can inform coping-based interventions for patients with systemic sclerosis.

Progression of Interstitial Lung Disease in Systemic Sclerosis: The Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18.

OBJECTIVE: To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS: Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS: Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION: In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

An Interim Report of the Scleroderma Clinical Trials Consortium Working Groups.

The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.

Cyclophosphamide for Systemic Sclerosis-related Interstitial Lung Disease: A Comparison of Scleroderma Lung Study I and II.

OBJECTIVE: To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II. METHODS: Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 mos) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity. RESULTS: SLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group. CONCLUSION: Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis-ILD.

Minimal Clinically Important Differences for the Modified Rodnan Skin Score: Results from the Scleroderma Lung Studies (SLS-I and SLS-II).

OBJECTIVE: This study aimed to assess the minimal clinically important differences (MCIDs) for the modified Rodnan skin score (mRSS) using combined data from the Scleroderma Lung Studies (I and II). METHODS: MCID estimates for the mRSS at 12 months were calculated using three anchors: change in scores on the Health Assessment Questionnaire- Disability Index from baseline to 12 months, change in scores on the Patient Global Assessment from baseline to 12 months, and answer at 12 month for the Short Form-36 health transition question "Compared to one year ago, how would you rate your health in general now?" We determined the mRSS MCID estimates for all participants and for those with diffuse cutaneous systemic sclerosis (dcSSc). We then assessed associations between MCID estimates of mRSS improvement and patient-reported outcomes, using Student's t test to compare the mean differences in patient outcomes between those who met the MCID improvement criteria versus those who did not meet the improvement criteria. RESULTS: The mean (SD) mRSS at baseline was 14.75 (10.72) for all participants and 20.93 (9.61) for those with dcSSc. The MCID estimate for mRSS improvement at 12 months ranged from 3 to 4 units for the overall group (improvement of 20-27% from baseline) and was 5 units for those with dcSSc (improvement of 24% from baseline). Those who met the mRSS MCID improvement criteria had statistically significant improvements in scores on the Short Form-36 Physical Component Summary, the Transition Dyspnea Index, and joint contractures at 12 months. CONCLUSION: MCID estimates for the mRSS were 3-4 units for all participants and 5 units for those with dcSSc. These findings are consistent with previously reported MCID estimates for systemic sclerosis.

Determining progression of scleroderma-related interstitial lung disease.

Interstitial lung disease occurs in the majority of patients with systemic sclerosis. Although interstitial lung disease is the number one cause of death in systemic sclerosis, interstitial lung disease progression rates vary considerably among patients with systemic sclerosis. Some patients with systemic sclerosis-associated interstitial lung disease have sub-clinical disease and may not derive benefit from immunosuppression, while others have a more aggressive interstitial lung disease phenotype. Reliable predictors of interstitial lung disease progression are lacking. The present review describes our current approach to monitoring systemic sclerosis-associated interstitial lung disease progression in clinical practice. To illustrate the marked heterogeneity that exists in interstitial lung disease progression rates in systemic sclerosis, this review presents the individual disease course of five unique patients with systemic sclerosis-associated interstitial lung disease who participated in the Scleroderma Lung Study II. These cases illustrate that treatment response rates vary in systemic sclerosis-associated interstitial lung disease and more research is needed to determine how to predict treatment response in systemic sclerosis-associated interstitial lung disease and to develop personalized treatment approaches for patients with this devastating disease.

Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts.

OBJECTIVE: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling. RESULTS: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data. CONCLUSION: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

An Interesting Case of Neurobrucellosis Mimicking Neuropsychiatric Lupus.

This case describes a patient presenting with acute onset papilledema, subacute strokes resulting in upper extremity weakness and numbness, arthritis, maculopapular rash, depressed C4 and CH50, and a high titer anti-double-stranded DNA antibody. The patient was given the diagnosis of probable systemic lupus erythematosus, which was supported by the Systemic Lupus International Collaborating Clinics (SLICC) criteria. He was aggressively treated for neuropsychiatric lupus (NPSLE) with pulse dose steroids and a dose of intravenous cyclophosphamide. Blood cultures drawn on admission later grew out 2/4 bottles of Gram-variable bacteria, speciated as Brucella melitensis by PCR. Serum Brucella serologies were also positive. On further evaluation, the patient noted a history of eating unpasteurized cheese in Mexico. Given these additional findings, the patient's presentation was most consistent with a diagnosis of neurobrucellosis. Steroids were tapered off, no further doses of cyclophosphamide were given, and a prolonged course of intravenous and oral antibiotic therapy was administered, resulting in complete resolution of the patient's presenting symptoms.

Etiology unknown: Qualitative analysis of patient attributions of causality in scleroderma.

Background: Questions about the etiology of disease can concern patients living with any chronic disease and may impact disease-related adjustment. These causal attributions may be of particular interest when individuals are living with diseases for which etiologies have not been definitively identified, such as scleroderma. This study qualitatively explored patient attributions of causality for scleroderma. Methods: Patients with confirmed diagnoses of scleroderma responded to an open-ended prompt. The cross-sectional sample of scleroderma patients (N = 114) was recruited through registries maintained at the University of California, Los Angeles and University of California, San Diego Schools of Medicine and the Virginia Mason Medical Center. Content analysis was used to analyze the qualitative data and group the responses via an inductively derived codebook using the text analysis tool Dedoose Version 4.5. Results: Patients provided a variety of possible causes for scleroderma, which grouped into seven themes: (1) stress, (2) environment, (3) genetics, (4) medical conditions or surgeries, (5) diet, (6) medications or substance use, and (7) spirituality. Conclusion: Patients' causal attributions for scleroderma were varied, but many patients identified stress as a cause of scleroderma, often focusing on acute or chronic stressors that were present before disease onset. Identifying patient theories of causality for scleroderma can contribute to an increased understanding of disease-related behaviors and adjustment.

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

OBJECTIVES: To assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II. METHODS: Using 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. RESULTS: Reliability 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. CONCLUSION: FVC% 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.

Efficacy of Mycophenolate Mofetil and Oral Cyclophosphamide on Skin Thickness: Post Hoc Analyses From Two Randomized Placebo-Controlled Trials.

OBJECTIVE: To assess the efficacy of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) on modified Rodnan skin score (MRSS) in participants enrolled in the Scleroderma Lung Study (SLS) I and II. METHODS: SLS I participants received daily oral CYC or matching placebo for 1 year, whereas SLS II participants received daily MMF for 2 years or daily oral CYC for 1 year followed by placebo for second year. We assessed the impact of MMF and CYC on the MRSS in SLS II over a 24-month period. We also compared the change in MRSS in patients with diffuse cutaneous systemic sclerosis (dcSSc) assigned to CYC and MMF in SLS II and SLS I versus placebo in SLS I over a 24-month period using a linear mixed model. RESULTS: In SLS II, the baseline mean ± SD MRSS was 14.0 ± 10.6 units for CYC and 15.3 ± 10.4 units for MMF; 58.5% were classified as dcSSc. CYC and MMF were associated with statistically significant improvements in MRSS from baseline over the period of 24 months in dcSSc (P < 0.05 at each time point), but there were no differences between the 2 groups. In the dcSSc subgroup, the change in MRSS from baseline to all 6-month visits was similar in SLS II groups (MMF, CYC, pooled cohort [MMF + CYC]) and in the SLS I CYC group and showed statistically significant improvements compared to SLS I placebo at 12, 18, and 24 months (P < 0.05). CONCLUSION: In SLS II, MMF and CYC treatment resulted in improvements in MRSS in patients with dcSSc over 24 months. In addition, MMF and CYC treatment resulted in statistically significant improvements in MRSS in patients with dcSSc when compared with the SLS I placebo group.

Muscle involvement in systemic sclerosis: points to consider in clinical trials.

SSc is clinically and pathogenetically heterogeneous. Consensus standards for trial design and outcome measures are needed. International experts experienced in SSc clinical trial design and a researcher experienced in systematic literature review screened the PubMed and Cochrane Central Register of Controlled Trials in order to develop points to consider when planning a clinical trial for muscle involvement in SSc. The experts conclude that SSc-associated muscle involvement is heterogeneous and lacks a universally accepted gold-standard for measuring therapeutic response. Although outcome studies are currently limited by the inability to clearly distinguish active, reversible muscle inflammation from irreversible muscle damage and extramuscular organ involvement, strong consideration should be given to enrolling patients with a myopathy that features several elements of likely reversibility such as muscle weakness, biopsy-proven active inflammation, an MRI indicating muscle inflammation and a baseline serum creatinine kinase above three times the upper limit of normal to prevent floor effect. Randomized controlled trials are preferred, with a duration of at least 24 weeks. Outcome measures should include a combination of elements that are likely to be reversible, such as muscle weakness, biopsy-proven active inflammation, creatinine kinase/aldolase and a quality of life questionnaire. The individual measurements might require a short pre-study for further validation. A biological sample repository is recommended.

Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts.

OBJECTIVE: To compare faecal microbial composition in patients with systemic sclerosis (SSc) from 2 independent cohorts with controls and to determine whether certain genera are associated with SSc-gastrointestinal tract (GIT) symptoms. DESIGN: Adult patients with SSc from the University of California, Los Angeles (UCLA) and Oslo University Hospital (OUH) and healthy controls participated in this study (1:1:1). All participants provided stool specimens for 16S rRNA sequencing. Linear discriminant analysis effect size demonstrated genera with differential expression in SSc. Differential expression analysis for sequence count data identified specific genera associated with GIT symptoms as assessed by the GIT 2.0 questionnaire. RESULTS: The UCLA-SSc and OUH-SSc cohorts were similar in age (52.1 and 60.5 years, respectively), disease duration (median (IQR): 6.6 (2.5-16.4) and 7.0 (1.0-19.2) years, respectively), gender distribution (88% and 71%, respectively), and GIT symptoms (mean (SD) total GIT 2.0 scores of 0.7 (0.6) and 0.6 (0.5), respectively). Principal coordinate analysis illustrated significant microbial community differences between SSc and controls (UCLA: p=0.001; OUH: p=0.002). Patients with SSc had significantly lower levels of commensal genera deemed to protect against inflammation, such as Bacteroides (UCLA and OUH), Faecalibacterium (UCLA), Clostridium (OUH); and significantly higher levels of pathobiont genera, such as Fusobacterium (UCLA), compared with controls. Increased abundance of Clostridium was associated with less severe GIT symptoms in both cohorts. CONCLUSIONS: The present analysis detected specific aberrations in the lower GIT microbiota of patients with SSc from 2 geographically and ethnically distinct cohorts. These findings suggest that GIT dysbiosis may be a pathological feature of the SSc disease state.