Systemic Sclerosis-associated Interstitial Lung Disease Patients Research Articles

Dysregulation of TNF-induced protein 3 and CCAAT/enhancer-binding protein β in alveolar macrophages: Implications for systemic sclerosis-associated interstitial lung disease.

This study investigates the role of TNF-induced protein 3 (TNFAIP3) and CCAAT/enhancer-binding protein β (C/EBPβ) in alveolar macrophages (AMs) of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) and their influence on pulmonary fibrosis. Transfection of HEK293T cells and AMs with plasmids carrying TNFAIP3 and C/EBPβ was performed, followed by co-culturing AMs with pulmonary fibroblasts. Immunoblotting analysis was then utilized to assess the expression of TNFAIP3, C/EBPβ, and collagen type 1 (Col1). Quantitative PCR analysis was conducted to quantify the mRNA levels of C/EBPβ, IL-10, and TGF-β1. STRING database analysis, and immunoprecipitation assays were employed to investigate the interactions between TNFAIP3 and C/EBPβ. TNFAIP3 expression was significantly reduced in SSc-ILD AMs, correlating with increased Col1 production in fibroblasts. Overexpression of TNFAIP3 inhibited this pro-fibrotic activity. Conversely, C/EBPβ expression was elevated in SSc-ILD AMs, and its reduction through TNFAIP3 restoration decreased pro-fibrotic cytokines IL-10 and TGFβ1 levels. Protein-protein interaction studies confirmed the regulatory relationship between TNFAIP3 and C/EBPβ. This study highlights the important role of TNFAIP3 in regulating pulmonary fibrosis in SSc-ILD by modulating C/EBPβ expression in AMs. These findings suggest that targeting TNFAIP3 could be a potential therapeutic strategy for managing SSc-ILD patients.

Lung ultrasound and high-resolution computed tomography quantitative variations during nintedanib treatment for systemic sclerosis-associated interstitial lung disease.

Lung ultrasound (LUS) and high-resolution computed tomography (HRCT) are commonly used for the evaluation of interstitial lung disease (ILD). Nintedanib (NIN) is an antifibrotic therapy approved for systemic sclerosis-associated ILD (SSc-ILD). We assessed LUS and quantitative HRCT changes in SSc-ILD patients treated with NIN during a one-year follow-up, evaluating relationships between imaging variations and functional or quality-of-life outcomes. SSc-ILD patients who started NIN were enrolled and followed for twelve months. Pulmonary function tests and patient-reported outcome measures (PROMs) were assessed half-yearly and quarterly, respectively. LUS was performed quarterly evaluating the presence of B-lines (BL) and pleural line irregularities (PLI). HRCT was repeated after one year and quantitatively analysed with CALIPER software. Ten patients (70% female, mean age 62 years) were enrolled. The mean total number of both BL and PLI was constantly decreased during NIN treatment, being significantly reduced after twelve months (from 175.1 ± 66.7-120.8 ± 70.3 for BL, p= 0.005 and from 50.6 ± 32.5-37.2 ± 22.4 for PLI, p= 0.05). Male gender, smoking habit and baseline forced vital capacity <70% predicted were associated with worse LUS outcomes. A greater reduction of both BL and PLI was observed in those who improved in PROMs, especially modified Medical Research Council dyspnoea scale (p= 0.016 and p= 0.04, respectively) and Saint George's Respiratory Questionnaire (p= 0.006 and p= 0.026, respectively). No significant changes in the CALIPER percentages of normal parenchyma or ILD elements were observed after twelve months of NIN, thus paralleling the stabilization obtained at pulmonary function tests. We present preliminary results on NIN effects on SSc-ILD as assessed by LUS, a useful method for frequently repeated monitoring, and CALIPER, a valid implementation whenever a HRCT is performed.

Circulating Biomarkers and Disease Activity in Systemic Sclerosis-Associated Interstitial Lung Disease

Background: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a major cause of death in SSc patients. Several studies have reported that serum anti-Scl-70, Krebs von Lungren-6 (KL-6), and surfactant protein D (SP-D) levels are associated with the presence and progression of ILD in SSc patients. Objective: To examine the correlation between levels of these serum biomarkers and disease severity determined by baseline dyspnea index (BDI), high-resolution computed tomography (HRCT) score, and pulmonary function tests. Materials and Methods: The present study was a single-center, cross-sectional study. Serum anti-Scl-70, KL-6, and SP-D from 20 SSc-ILD patients and five non-ILD subjects were measured. The BDI, HRCT score, and pulmonary function tests were used to assess the severity of ILD in SSc-ILD patients. HRCT abnormalities, including ground-glass opacity (GGO), fibrosis, and honeycombing, were scored by using the semi-quantitative scoring system. Results: Serum anti-Scl-70, KL-6, and SP-D in SSc-ILD patients were significantly higher than those in non-ILD subjects. There was a moderate correlation between diffusing capacity for carbon monoxide (DLCO) and serum KL-6 levels (r=–0.551, p=0.022), while the pulmonary fibrosis (PF) score exhibited a strong correlation with serum KL-6 levels (r=0.630, p=0.003). The PF score had a moderate negative correlation with forced vital capacity (FVC) (r=–0.515, p=0.034) and a strong negative correlation with total lung capacity (TLC) and DLCO (r=–0.625, p=0.007, and r=–0.762, p&lt;0.001, respectively). Conclusion: The levels of serum KL-6, and SP-D are elevated in SSc-ILD patients. Serum KL-6 may be a useful non-invasive biomarker for the disease severity, as determined by DLCO and the extent of fibrosis on HRCT, in patients with SSc-ILD. Trial registration: Thai Clinical Trials Registry, TCTR20200314001, registered 13 March 2020, retrospectively registered at http://www.thaiclinicaltrials.org/show/TCTR20200314001 Keywords: Scleroderma; Systemic sclerosis; Interstitial pneumonia; Interstitial lung disease; Fibrosis; Biomarker

Mediators of systemic sclerosis-associated interstitial lung disease (SSc-ILD): systematic review and meta-analyses

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is rare, poorly understood, with heterogeneous characteristics resulting in difficult diagnosis. We aimed to systematically review evidence of soluble markers in peripheral blood or...

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Systemic sclerosis related interstitial lung disease and nintedanib

Although many mechanisms leading to lung fibrosis in systemic sclerosis-associated interstitial lung disease (SSc-ILD) have been suggested, this issue has not been fully understood yet. Recently, there has been increased evidence that the mediators and pathological mechanisms responsible for idiopathic pulmonary fibrosis (IPF) are similar to those in SSc-ILD. Accordingly, studies have been conducted to support that antifibrotic agents used in the treatment of IPF may also be useful in SSc-ILD. There are currently two antifibrotic agents on the market, namely nintedanib and pirfenidon. Although studies on the use of pirfenidone in SSc-ILD are not satisfactory, nintedanib studies have yielded positive results. The SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) study is the first and most comprehensive Phase III study on this subject. In 2019, the results of SENSCIS trial showed that, nintedanib significantly reduced the annual decline in lung function in SSc-ILD. After this trial, which did not include SSc-ILD patients with severe lung function loss, nintedanib licenced for the treatment of SSc-ILD worldwide. However, the currently available literature data lacks information about long-term effects and side effects of nintedanibe on SSc-ILD an also about the advanced SSc-ILD. The aim of this study is to review SSc-ILD patients treated with nintedanib, by also mentioning the pathogenesis of this disease according to the current literature.

POS0063 PROGRESSIVE INTERSTITIAL LUNG DISEASE IS FREQUENT ALSO IN LATE DISEASE STAGES IN SYSTEMIC SCLEROSIS PATIENTS FROM EUSTAR

BackgroundShort disease duration is a predictor for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD), but studies assessing ILD progression in later disease stages are lacking. To individually tailor management of ILD in SSc patients in clinical practice it is, however, of high importance to understand disease behaviour also in patients with late disease.ObjectivesAnalyse ILD progression in SSc-ILD patients from the EUSTAR cohort segregated by subgroups of disease duration.MethodsWe segregated SSc-ILD patients into four categories of disease duration (≤3 years, &gt;3- ≤7 years, &gt;7- ≤15 years and &gt;15 years after onset of Raynaud’s phenomenon). We assessed progressive ILD, defined as forced vital capacity (FVC) decline &gt;10% or FVC decline ≥10% and FVC decline 5–10% and diffusing capacity of the lungs for carbon monoxide (DLCO) decline ≥15% (composite decline) over the first and second 12+/-3 months period after first registration (baseline) into EUSTAR. Clinical characteristics, pulmonary involvement, treatment at first registration and ILD progression were evaluated by descriptive statistics.ResultsIn total, 2258 SSc-ILD patients were included, with 469 (20.8%) having a disease duration ≤3 years, 550 (24.4%) between &gt;3- ≤7 years, 752 (33.3%) between &gt;7- ≤15 years and 488 (21.6%) of &gt;15 years (Table 1). Baseline characteristics and treatment patterns differed between the four subgroups, with more younger male patients with diffuse cutaneous SSc, anti-topoisomerase I antibody and higher Rodnan skin score having ≤3 years disease duration. Lung function with FVC and DLCO were similar between the four groups (Table 1). Notably, in the first and second 12+/-3 months periods after first registration in the EUSTAR database, there were no significant difference in FVC decline &gt;10% or composite FVC and DLCO decline within the four subgroups. For example, patients with disease duration &gt;7- ≤15 years and &gt;15 years frequently showed disease progression of FVC &gt;10%: 41/347 (11.8%) and 32/228 (14%) compared to 38/244 (15.6%) and 33/273 (15.6%) for disease duration ≤3 years and &gt;3- ≤7 years (P=0.529), respectively (Figure 1).Table 1.Demographics and baseline clinical characteristics of EUSTAR patientsDisease duration≤ years(n=460)&gt;3- ≤7 years(n=550)&gt;7- ≤15 years(n=752)&gt;15 years(n=488)p-valueAge, years (SD)55 (13.5)55 (14.1)57 (13.1)61 (11.5)&lt;0.001Male, n (%)123 (26.2)115 (20.9)112 (14.9)38 (7.8)&lt;0.001DcSSc, n (%)228 (56.4)262 (45.8)311 (45.4)163 (31.2)&lt;0.001ATA, n (%)236 (53.4)293 (55.9)374 (52.8)218 (48.0)0.099mRSS, mean (SD)12.3(10.1)10.4 (8.3)9.4 (8.1)8.7 (7.7)&lt;0.001GERD, n/N (%)273 (58.7)353 (64.4)482 (64.4)344 (71.2)0.001ESR, mean (SD)26.9(21.7)24.2 (19.5)26.2 (19.9)28.3 (21.2)0.022MMF, n/N (%)33 (16.6)43 (25.2)37 (20.4)14 (9.3)0.002MTX, n/N (%)19 (10)17 (10.1)19 (10.6)8 (5.2)0.296Any IS, n/N (%)81 (38.6)89 (47.1)82 (40.8)46 (28.7)0.006FVC % pred, mean (SD)86 (20.9)87 (21.6)86 (21.4)87 (22.8)0.770DLCO % pred, mean (SD)58 (19.3)59 (19.3)59 (19.9)58 (19.7)0.405NYHA class 3&amp;4, n (%)84 (18.6)78 (14.6)125 (17.5)22.6 (7.0)0.090Figure 1.FVC decline &gt;10% and composite FVC and DLCO decline in the first and second 12+/-3 months within the four subgroups segregated by disease durationConclusionIt was long believed that ILD burned out in late disease stages. In our analysis of ILD progression by four disease duration categories, we showed that ILD frequently progressed also in late disease stages. This has important implications for clinical practise, as SSc patients need to be regularly monitored for ILD progression independent of disease duration.Disclosure of InterestsAnna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp &amp; Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp &amp; Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Paolo Airò Speakers bureau: Bristol-Myers-Squibb, Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Grant/research support from: Bristol-Myers-Squibb, Roche, Jannsen, CSL Behring, Lidia P. Ananyeva Speakers bureau: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, László Czirják Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Roche, Lilly, Grant/research support from: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Serena Guiducci: None declared, Eric Hachulla Speakers bureau: GSK, Roche-Chugai, Johnson &amp; Johnson, Boehringer Ingelheim, Consultant of: CSL Behring, GSK, Roche-Chugai, Johnson &amp; Johnson, Boehringer Ingelheim, Grant/research support from: CSL Behring, Boehringer Ingelheim, GSK, Roche-Chugai, Sanofi Genzyme, Mengtao Li: None declared, Carina Mihai Speakers bureau: MEDtalks Switzerland, Mepha, Grant/research support from: Roche, Boehringer Ingelheim, Janssen, Gabriela Riemekasten Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Petros Sfikakis Consultant of: Boehringer Ingelheim, Gabriele Valentini Consultant of: Boehringer Ingelheim, Grant/research support from: Sanofi/BMS, Otylia Kowal-Bielecka Speakers bureau: Boehringer Ingelheim, Novartis, Pfizer, Gilead Sciences, Janssen-Cilag, MEDAC, MSD, Abbvie, Sandoz, Consultant of: Boehringer Ingelheim, Health Care system Navigator, CSL Behring, MSD, Novartis, Grant/research support from: CSL Behring, Boehringer Ingelheim, Abbvie, Roche, MEDAC, Yannick Allanore Speakers bureau: Boehringer, Abbvie, Consultant of: Boehringer, Bayer, Astra-Zeneca, Prometheus, Sanofi, Genentech/Roche, Boehringer, Grant/research support from: Alpine Immunosciences, OSE Immunotherapeutics, Medsenic, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim

Increased Red Blood Cell Distribution Width in the First Year after Diagnosis Predicts Worsening of Systemic Sclerosis-Associated Interstitial Lung Disease at 5 Years: A Pilot Study.

The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) varies among individuals. Red blood cell distribution width (RDW) has been reported to be a predictor of idiopathic pulmonary fibrosis. However, there are no studies on the relationship between RDW and SSc-ILD. We conducted a retrospective study of 28 patients who were diagnosed with SSc-ILD on their first visit to our hospital and were followed-up for 5 years. The correlation between the changes in RDW, KL-6, and SP-D (ΔRDW, ΔKL-6, ΔSP-D) and the changes in percent-predicted forced lung volume and % carbon monoxide diffusion (Δ%FVC, Δ%DLco) was investigated. ΔRDW at 1 year after diagnosis was significantly inversely correlated with Δ%FVC at 5 years after diagnosis (r = −0.51, p < 0.001) and Δ%DLco at 5 years after diagnosis (r = −0.47, p < 0.001), whereas ΔKL-6 and ΔSP-D at 1 year were not correlated with Δ%FVC or Δ%DLco at 5 years. In the group of SSc-ILD patients with RDW increase in the first year after diagnosis, %FVC and %DLco were significantly lower than baseline at 3-, 4-, and 5-year assessments. In the group of patients without RDW increase in the first year, %FVC and %DLco did not decrease during the follow-up period. In conclusion, the changes in RDW in the first year after diagnosis may be useful surrogate markers to predict the long-term course of SSc-ILD.

High-Resolution Computed Tomography: Lights and Shadows in Improving Care for SSc-ILD Patients.

The diagnosis and classification of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is essential to improve the prognosis of systemic sclerosis (SSc) patients. The risk-stratification of disease severity and follow-up requires a multidisciplinary approach, integrating high-resolution computed tomography (HRTC) of the lung, pulmonary function tests (PFT), along with clinical and symptomatic evaluations. The use of HRCT in detecting SSc-ILD is not so much based on a definitive validation, but rather reflects the widespread clinician recognition of dissatisfaction with other modalities. However, due to the heterogeneity of SSc-ILD and the potential absence of symptoms in early or mild disease, it is prudent to consider as many parameters as possible in the assessment and monitoring of newly diagnosed patients. An early diagnosis meets the primary goal, i.e., the prevention of disease progression. The current first line treatment regimens are mainly centered on immunosuppressive therapy. This review assesses the role HRCT plays in optimizing care and improving clinical outcomes in SSc-ILD patients.

Percentage of residual B cells after 2weeks of rituximab treatment predicts the improvement of systemic sclerosis-associated interstitial lung disease.

The benefit of rituximab (RTX) for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has been shown in previous clinical trials. However, predictors of RTX efficacy have not been clarified. We investigated whether B-cell responsiveness to RTX is related to therapeutic effect. Ten SSc-ILD patients treated with RTX in an independent clinical trial (Japan Registry of Clinical Trials, jRCTs031180373) were included in this analysis. Peripheral B-cell counts were examined retrospectively before RTX administration (baseline) and at 2, 4, 12, and 24weeks after the first RTX administration, along with percent-predicted forced vital capacity (%FVC) before and 24weeks after RTX treatment. Relative to baseline, the percentage of residual peripheral blood B cells at 2weeks after RTX was negatively correlated with the %FVC improvement at the 24-week assessment (r=-0.41, p=0.04). In the subgroup with less than 5% B-cell persistence at week 2, %FVC at the 24-week assessment was significantly improved compared to baseline (p=0.02). In another subgroup with more than 5% residual B cells, %FVC was not significantly different after 24weeks compared to baseline (p=0.41). In conclusion, the removal rate of B cells after 2weeks of RTX treatment may be a useful surrogate marker of subsequent SSc-ILD improvement.

PMS52 Quality of Life in Ssc-ILD Patients: Understanding the IMPACT of the ILD and the NEEDS of the Ssc-ILD Patients and Their Caregivers in France

The main objectives of this study were to describe the impact of Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD) on quality of life (QoL), to estimate the correlation between QoL and severity of lung disease and to assess the impact of ILD on caregivers. Seven investigators included SSc-ILD patients from December 2019 to April 2020. Sociodemographics and clinical data were collected. Patients reported outcomes (PROs) and questionnaires were used with 1 generic PRO (EQ-5D-5L), 1 specific PRO (K-BILD) and 2 self-reported questionnaires on impact of SSc complications and impact on caregivers. The correlation between forced vital capacity (FVC) and EQ-5D-5L score was estimated with a multivariate linear regression model adjusted on several covariates. 89 patients were included. 26.4% were males, mean age was 58±14.5 years. Mean EQ-5D-5L score=0.79±0.22 (median=0.85). Mean EQ-5D-5L VAS score=60.8±20.4 (median=61.5). Mean K-BILD score=58.4±12.7 (median=58.0). After adjustment on covariates, a significant correlation between FVC and EQ-5D-5L score was found with an increase of 0.003 of the EQ-5D-5L score for a 1% increase of FVC (p=0.01). No significant correlation between FVC and the EQ-VAS and K-BILD score were found. After adjustment, the impact of SSc on other organs was significantly correlated with EQ-5D-5L score respectively for the impact scores on the lung system (p=0.0013), heart system (p=0.002), Raynaud’s syndrome (p=0.0087), digestive system (p=0.0003), joints/muscles (p<0.0001), skin (p<0.0001), kidney (p=0.0004) and gastro-oesophageal reflux (p=0.0013) . Significant correlations between K-BILD score and lung system (p<0.0001), heart system (p<0.0001), digestive system (p<0.0001), kidney (p=0.0002), skin (p=0.03) and gastro-oesophageal reflux (p=0.0003) scores were also found 68.5% of patients reported their need for a caregiver to help them in their daily life activities. Our study highlighted the strong burden of SSc-ILD for patients, especially with an impact on QoL, on other organs manifestations and need for caregivers in their daily life.

Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database

ObjectivesTo identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), using data from the European Scleroderma...

Worsening of esophageal dilatation is associated with increase in a high-resolution computed tomography (HRCT) score in early systemic sclerosis-associated interstitial lung disease (SSc-ILD).

Data regarding longitudinal association between changes (Δ: time2-time1) in the widest esophageal diameter (WED) and Δ HRCT score in early SSc-ILD patients is limited. We therefore investigated the association of ΔWED with Δ HRCT score and predictors of a worse Δ HRCT score in those patients. We used an inception cohort of early SSc-ILD patients with availability for two HRCT records at enrollment and 1-year follow-up.The extent of ground glass, reticulation, bronchiectasis, and honeycombing was scored and then aggregated to produce a total HRCT score. The WED was measured at four levels and the maximum value was used. The Δ maximum WED, Δ mean WED, and Δ tHRCT score were analyzed. We recruited 75 early SSc-ILD patients and found a significant correlation of Δ tHRCT score with a Δ maximum WED (rho = 0.34, p < 0.01) and Δ mean WED (rho = 0.26, p < 0.05). There were 34 patients with a worsening Δ tHRCT (Δ > 0), 17 with stability (Δ = 0), and 24 with improvement (Δ < 0). Patients with a worsening ILD had a significantly shorter disease duration, lower prevalence of tendon friction rub, higher cumulative prednisolone dose, and larger ΔWED than those with stable and improved Δ tHRCT scores. Multivariate ordinal logistic regression identified a larger Δ mean WED (OR 1.21, 95% CI 1.03-1.42, p = 0.02) as a predictor of worsening HRCT score, while presence of tendon friction rub was associated with a lower risk (OR 0.18, 95% CI 0.04-0.77, p = 0.021). Our study cohort found that a worsening esophageal diameter was a predictor of progression of lung fibrosis determined by HRCT score in early SSc-ILD. A further study regarding esophageal dilation progression different in early versus longstanding SSc-ILD is needed. Key Points •In early SSc-ILD patients, we demonstrated that a worsening esophageal diameter was a predictor of progression of HRCT score at 1-year follow-up. •Further study regarding the association of worsening of the esophageal dilatation with the progression of ILD comparing between early versus late SSc-ILD is needed.

Evaluation of mean platelet volume before and after cyclophosphamide treatment in systemic sclerosis associated interstitial lung disease

Aim: Studies carried out in patients with systemic sclerosis (SSc) have shown that mean platelet volume (MPV) is associated with more advanced stage of SSc. However, the effect of cyclophosphamide (CP) on MPV in systemic sclerosis-associated interstitial lung disease (SSc-ILD) is less clear. In this study, we aimed to investigate the MPV response to CP treatment in SSc-ILD. Methods: Thirty-eight SSc-ILD patients who responded positively to CP were included in this retrospective cohort study. MPV values before the treatment were compared with third, sixth, and ninth months’ values during treatment. Results: Over the nine-year period, 82 patients were diagnosed with SSc in the rheumatology clinic of our hospital. Forty-three of them had SSc-ILD and all were administered CP treatment for 9 months. Thirty-eight clinically benefited from CP, among which 32 were females (84%) and 6 (16%) were males. The MPV levels in SSc-ILD patients after CP (9.44 fL) were significantly higher than those before CP (7.89 fL) (P=0.001). Conclusion: Cyclophosphamide treatment causes an increase in MPV in SSc-ILD. MPV, a negative acute phase reactant, is considered an independent risk factor for coronary and peripheral artery diseases. Patients receiving CP should be followed more closely for such diseases.

Ability of the COPD Assessment Test to evaluate the lung-specific quality of life in systemic sclerosis-associated interstitial lung disease.

IntroductionThe COPD Assessment Test (CAT) is utilised to evaluate the treatment outcome regarding the health status in idiopathic interstitial pneumonia (IIP). However, the ability of the CAT to evaluate the lung‐specific quality of life in systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is not established. Therefore, we investigated whether CAT scores can be used to evaluate SSc‐ILD as they are for IIP.MethodsA total of 150 patients with IIP or SSc‐ILD who were evaluated by the CAT were retrospectively assigned to this study. Clinical data at the visit for the CAT were analysed.ResultsThe forced vital capacity and distance walked during the 6‐minute walk test (6MWD) were significantly correlated with the CAT score for SSc‐ILD and IIP, and the CAT scores were similarly distributed in SSc‐ILD and IIP. The CAT score of SSc‐ILD patients was negatively affected by pulmonary arterial hypertension, but not by corticosteroids, which affected it in IIP patients. CAT scores of patients with either disease receiving home oxygen therapy were poor. In multiple regression analysis, pulmonary arterial hypertension and 6MWD were independent predictors for the CAT score in patients with SSc‐ILD, while corticosteroid administration was selected as an independent factor in patients with IIP.ConclusionsOur study suggests that the CAT can be applied to evaluate the lung‐specific quality of life in SSc‐ILD similar to IIP regarding the pulmonary function, but it should be noted that pulmonary arterial hypertension in SSc‐ILD influences the CAT score.

The Chinese herb Tripterygium wilfordii Hook F for the treatment of systemic sclerosis-associated interstitial lung disease: data from a Chinese EUSTAR Center.

To assess the efficacy and safety of the Chinese herb Tripterygium wilfordii Hook F (TwHF) for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). SSc-ILD patients who were regularly treated for more than 1year and were currently taking a stable dose of TwHF (40-60mg/day) or CYC (100mg/day) were selected from the EUSTAR database of Peking Union Medical College Hospital. The efficacy of treatments was assessed by the change in pulmonary function, including the forced vital capacity (FVC) and the percentage of predicted FVC (FVC pred%). Among the 431 patients diagnosed with SSc-ILD, 76 fulfilled the inclusion and exclusion criteria. Twenty eight patients received TwHF monotherapy, while 48 received oral CYC monotherapy. Baseline data prior to treatment did not differ significantly between the two groups. After 1year of treatment, significant improvements in the FVC and FVC pred% were seen in both groups (P < 0.05) and the magnitude of improvement was comparable (P = 0.93). However, TwHF was only found to be effective in improving FVC and FVC pred% when administered as a maintenance therapy, but not as an induction therapy. No severe adverse events were seen in either group. Leucopenia occurred more often in the CYC group compared to the TwHF group (P = 0.034). TwHF may be considered as a potential alternative drug for SSc-ILD patients, especially as a maintenance therapy. A prospective randomized controlled trial is necessary to further confirm these results.Key Points• This is the first clinical study of Tripterygium wilfordii Hook F (TwHF) in the treatment of SSc-ILD, providing a novel therapeutic option for SSc-ILD.• TwHF shows a comparable therapeutic efficacy to CYC when treating SSc-ILD.• TwHF has unique therapeutic advantages considering the balance of economy and safety and may be a good potential choice for maintenance therapy.

Oesophageal diameter is associated with severity but not progression of systemic sclerosis-associated interstitial lung disease.

It is unknown whether oesophageal disease is associated with systemic sclerosis-associated interstitial lung disease (SSc-ILD) severity, progression or mortality. High-resolution computed tomography (HRCT) scans from 145 SSc-ILD patients were scored for fibrosis score, oesophageal diameter and presence of hiatal hernia. Fibrosis asymmetry was calculated as: (most affected side - least affected side)/(most affected side + least affected side). Mixed effects models were used for repeated measures analyses. Mean fibrosis score was 8.6%, and most patients had mild-to-moderate physiological impairment. Every 1 cm increase in oesophageal diameter was associated with 1.8% higher fibrosis score and 5.5% lower forced vital capacity (FVC; P ≤ 0.001 for unadjusted and adjusted analyses). Patients with hiatal hernia had 3.9% higher fibrosis score, with persistent differences on adjusted analysis (P = 0.001). Oesophageal diameter predicted worsening fibrosis score over the subsequent year (P = 0.02), but not when adjusting for baseline fibrosis score (P = 0.16). Oesophageal diameter was independently associated with mortality (P = 0.001). Oesophageal diameter was not associated with asymmetric disease or radiological features of gross aspiration. Oesophageal diameter and hiatal hernia are independently associated with SSc-ILD severity and mortality, but not with ILD progression or asymmetric disease. Oesophageal disease is unlikely to be a significant driver of ILD progression in SSc.

Anti-fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis-associated interstitial lung disease.

To determine whether pirfenidone attenuates lung fibrosis by interfering with the hedgehog (Hh) signalling pathway in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Twenty-five SSc-ILD patients (20 first visit, five who underwent pirfenidone treatment for 6 months) and 10 healthy controls were recruited. Lung tissues were obtained by open-chest surgery, and primary lung fibroblasts were isolated, cultured and stimulated with pirfenidone. The levels of the proteins glioma-associated oncogene 1 (GLI1), suppressor of fused (Sufu), α-smooth muscle actin, and fibronectin in lung tissues or fibroblasts were determined by Western blotting. The messenger RNA levels of GLI1, glioma-associated oncogene 2, protein patched homolog 1, and Sufu in lung tissues or fibroblasts were determined by quantitative reverse-transcription polymerase chain reaction. Meanwhile, the levels of phosphorylation glycogen synthase kinasep-3β (pGSK-3β), phosphorylation SMAD2 (pSMAD2), and phosphorylation c-Jun N-terminal kinase (pJNK) in fibroblasts were determined by Western blotting. Hh pathway activation was increased in the lung tissue of SSc-ILD patients and was decreased by pirfenidone, Sufu was upregulated in lung fibroblasts isolated from SSc-ILD patients after pirfenidone challenge, and pirfenidone inhibited the phosphorylation of GSK-3β signalling. Pirfenidone has anti-fibrotic effects in SSc-ILD patients by interfering with both the Hh signalling pathway and the GSK-3β signalling pathway via the regulation of Sufu expression. These results might promote its use in other Hh driven lung diseases such as idiopathic pulmonary fibrosis and especially the interstitial lung disease associated with connective tissue diseases.

A retrospective cohort study of outcome in systemic sclerosis-associated interstitial lung disease.

The relationship between the histological pattern and survival in systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unclear. In patients with SSc-ILD, we investigated whether the clinical data obtained by non-invasive examinations could be used for prognostic evaluation, and attempted to clarify whether complicating acute exacerbation (AE) and the selection of pharmacological therapy were associated with survival. Thirty-five patients with SSc-ILD, who had not been diagnosed by surgical lung biopsy were analyzed, retrospectively. The HRCT findings were evaluated by 2 radiologists and classified into "CT-UIP" or "CT-inconsistent with UIP" patterns based on whole lung interpretations. HRCT scores were calculated based on the extent of abnormality evidenced by HRCT. The log-rank test was used to determine variables, including clinical parameters and histories. Twelve (34%) of the 35 patients died during a median follow-up period of approximately 7.9 years. The log-rank test showed that a higher mortality was associated with higher age, a CT-UIP pattern, a higher score for ground-glass attenuation with traction bronchiectasis on HRCT, and complicating AE, whereas a lower mortality was significantly associated with the use of immunosuppressants. A CT-UIP pattern was significantly associated with a higher incidence of later AE. Treatment with immunosuppressants was associated with a longer survival, and complicating AE is a predictor of shortened survival in SSc-ILD patients. Among the clinical parameters determined by non-invasive examinations, a CT-UIP pattern and the extent of fibrotic lesions on HRCT, but not a histological pattern of UIP, may be predictors of shortened survival.

Outcome of systemic sclerosis associated interstitial lung disease treated with intravenous cyclophosphamide

Our objective was to audit the respiratory outcome, toxicity and long-term survival of systemic sclerosis associated interstitial lung disease (SSc-ILD) treated with intravenous (i.v.) cyclophosphamide. We ascertained whether i.v. cyclophosphamide associates with a better outcome in SSc-ILD diagnosed due to a decline in screening lung function than in those diagnosed due to respiratory symptoms. A retrospective case-note audit was carried out for SSc-ILD patients treated with i.v. cyclophosphamide between January 1999 and March 2009 at the Royal Derby, Kings Mill and Nottingham University Hospitals. Forced vital capacity (FVC) and transfer factor at 6, 12months after starting i.v. cyclophosphamide were the primary end points. Kaplan-Meier curves were plotted to estimate survival. Thirty-seven i.v. cyclophosphamide treatment cycles were administered to 36 patients (27 women). Fourteen cycles associated with side effects and eight were terminated prematurely. SSc-ILD was diagnosed due to respiratory symptoms in 13 and in response to deteriorating screening pulmonary function test (PFT) in 24 instances. Overall, i.v. cyclophosphamide led to stabilisation in lung function. However, the FVC declined by 7% in SSc-ILD presenting with respiratory symptoms over 12months. These patients had significantly lower FVC at 6 and 12month than those with SSc-ILD diagnosed due to decline in screening lung function. The 5-year survival was 76.1% (overall), 62.9% (diagnosed due to respiratory symptoms) and 91.5% (diagnosed due to decline in screening lung function, p = 0.05). I.V. cyclophosphamide stabilises lung function in individuals with SSc-ILD and may associate with better respiratory outcome in patients diagnosed on screening PFTs.