Tracy M. Frech

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

Summary BACKGROUND Twelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC. METHODS Patients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129, and is closed. RESULTS Between November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores. INTERPRETATION Treatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to its better tolerability and toxicity profile. FUNDING National Heart, Lung and Blood Institute/National Institutes of Health with drug supply provided by Hoffmann-La Roche/Genentech.

Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry.

To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.

Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry

Background Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21–24 mm Hg) are “at risk” of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics. Methods PHAROS is a multicentre prospective longitudinal cohort of patients with SSc “at risk” or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups. Results 206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP 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 borderline mPAP group and 32% of the normal group developed resting PH (p=NS). Conclusions Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.

Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study.

OBJECTIVE To investigate the familiality of systemic sclerosis (SSc) in relation to Raynauds phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD). METHODS A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated. RESULTS A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was approximately 8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99-3.41], P = 2.42 x 10(-15)) and second-degree relatives (1.48 [95% CI 1.34-2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44-11.83], P = 4.04 x 10(-9)) and second-degree relatives (2.39 [95% CI 1.21-4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04-2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18-1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06-1.35], P = 0.004). CONCLUSION These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives.

Prevalence and correlates of sleep disturbance in systemic sclerosis—results from the UCLA scleroderma quality of life study

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 Spearmans 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.

Measuring response in the gastrointestinal tract in systemic sclerosis.

Purpose of reviewGastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials. Recent findingsPatient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials. SummaryGIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc.

Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

Objectives Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. Methods Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. Results Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. Conclusions Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. Trial registration number NCT01532869; Results.

Antinuclear antibody-negative systemic sclerosis.

OBJECTIVE To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. METHODS SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. RESULTS This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28). CONCLUSIONS In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

Vascular leak is a central feature in the pathogenesis of systemic sclerosis.

Objective. The main histopathological focus of systemic sclerosis (SSc) has concentrated on fibrotic changes. We investigated the microvasculature alterations in the skin of patients with SSc at various stages of disease duration with whole-field digital microscopy. Methods. Twenty consecutive patients with SSc, 1 with Raynaud’s phenomenon (RP) without SSc, and 4 healthy controls underwent punch biopsy on the medial forearm. Eighteen patients were included in the primary analysis. Two with recent-onset diffuse cutaneous disease, 1 repeat SSc biopsy, and 1 patient with RP without SSc were also evaluated. All specimens were processed with histochemical stains and immunohistochemistry. We analyzed microvasculature abnormalities in an objective and systematic manner taking advantage of recent advances in whole-field digital microscopy. This analysis was coupled with ultrastructural evaluation performed with transmission electron microscopy (TEM). Results. Whole-field digital microscopy and TEM of SSc skin biopsies revealed that endothelial abnormalities are a universal feature regardless of clinical features and/or duration of disease. These features were not seen in any healthy control specimens or in the single RP patient samples. Whole-field digital microscopy identified increased interstitial edema (31.0% ± 9.6% vs 17.6% ± 3.3% in controls; p = 0.009) and fibrosis (75.6% ± 5.7% vs 66.1% ± 9.8% in controls; p = 0.02) in all patients with SSc. Lower CD34 staining was seen in SSc compared to healthy controls (0.32% ± 0.22% vs 1.31% ± 0.34%; p < 0.0001) and within the SSc population with interstitial lung disease (0.55% ± 0.22% vs 0.15% ± 0.16%; p = 0.01). Perivascular and interstitial infiltrate of mast cells was present in all SSc specimens. Conclusion. Whole-field digital microscopy offers a means of rapidly carrying out objective, fully quantitative, and reproducible measurements of microscopic features of SSc microvascular change. The universal morphologically abnormal endothelial cells and interstitial edema in all patients with SSc biopsied suggests that SSc may be intrinsically a disease of the endothelium characterized by vascular leak.