Scleroderma Interstitial Lung Disease Research Articles

Type 2 cytokines and scleroderma interstitial lung disease.

Interstitial lung disease (ILD) is a life-threatening complication of systemic sclerosis (SSc). Type 2 (Th2) cytokines play a pivotal role in airway disease. Study aim was to evaluate serum level of Th2 interleukin (IL) and chemokine in SSc-ILD. Serum levels of IL-4, IL-5, IL-11, IL-13, IL-21, IL-31 and CXCL-13 were measured by Bio-Plex Multiplex Immunoassays in 60 SSc patients and 20 healthy controls (HC). Pulmonary function tests with diffusion lung capacity for carbon monoxide (DLco) and high resolution computed tomography (HRCT) were performed in SSc patients. ILD is defined as fibrotic changes (ground glass, reticular and honeycombing), assessed by Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) software, affecting at least 10% of the lungs. Serum levels of Th2 cytokines were higher in SSc patients than HC. A linear correlation was observed between ground glass and IL-13 (r = 0.342, p < 0.01), IL-21 (r = 0.345, p < 0.01), IL-31 (r = 0.473, p < 0.001), IL-4 (r = 0.863, p < 0.001), IL-5 (r = 0.249, p < 0.05) and peripheral blood eosinophils (r = 0.463, p < 0.001). We found a negative correlation between DLco and IL-4 (r = - 0.511, p < 0.001) and peripheral blood eosinophils (r = - 0.446, p < 0.001). In the logistic regression analysis, IL-4 is associated with DLco ≤ 60% of the predicted [OR 1.039 (CI 95%: 1.015-1.064), p < 0.001], whilstmRSS [OR 1.138 (CI 95%: 1.023-1.266), p < 0.05] and IL-4 [OR 1.017 (CI 95%: 1-1.034), p < 0.05] were associated with ILD. Th2 inflammation could play a key role in early phase of SSc-ILD.

Alveolar epithelial-to-mesenchymal transition in scleroderma interstitial lung disease: Technical challenges, available evidence and therapeutic perspectives

The alveolar epithelial-to-mesenchymal transition is the process of transformation of differentiated epithelial cells into mesenchymal-like cells through functional and morphological changes. A partial epithelial-to-mesenchymal transition process can indirectly contribute to lung fibrosis through a paracrine stimulation of the surrounding cells, while a finalized process could also directly enhance the pool of pulmonary fibroblasts and the extracellular matrix deposition. The direct demonstration of alveolar epithelial-to-mesenchymal transition in scleroderma-related interstitial lung disease is challenging due to technical pitfalls and the limited availability of lung tissue samples. Similarly, any inference on epithelial-to-mesenchymal transition occurrence driven from preclinical models should consider the limitations of cell cultures and animal models. Notwithstanding, while the occurrence or the relevance of this phenomenon in scleroderma-related interstitial lung disease have not been directly and conclusively demonstrated until now, pre-clinical and clinical evidence supports the potential role of epithelial-to-mesenchymal transition in the development and progression of lung fibrosis. Evidence consolidation on scleroderma-related interstitial lung disease epithelial-to-mesenchymal transition would pave the way for new therapeutic opportunities to prevent, slow or even reverse lung fibrosis, drawing lessons from current research lines in neoplastic epithelial-to-mesenchymal transition.

B Cell Depletion Treatment in Resistant Systemic Sclerosis Interstitial Lung Disease.

Systemic sclerosis is a systemic, autoimmune disease that in many patients affects not only the skin, but also internal organs, mainly the lung. It is clear that internal organ (ie, lung) involvement determines the prognosis. Therefore, there is an unmet need to introduce novel and more effective treatments capable of halting disease progression and hence improve prognosis. Experimental data over the past decade has accumulated pointing to the B cell as a player in disease pathogenesis. Consequently, a number of controlled and uncontrolled studies have investigated the results of B cell depletion treatment in patients with SSc. The results are preliminary still encouraging for skin as well as for pulmonary involvement. In this review we will analyse and discuss such trials that have currently added B cell depletion as an alternative and promising treatment for resistant interstitial lung disease in scleroderma.

Outcome of pulse oral cyclophosphamide therapy in scleroderma interstitial lung disease.

Standard regimens for scleroderma interstitial lung diseases (SSc-ILDs) are pulse intravenous (IV) and oral daily cyclophosphamide (CYC). However, IV CYC has limited access to diffuse cutaneous SSc, and oral daily CYC is associated with febrile neutropenia and hemorrhagic cystitis. Pulse oral CYC regimen has never been studied. To determine the effectiveness of pulse oral CYC therapy in SSc-ILDs, predictors of effectiveness, and side-effects. A historical cohort study enrolled SSc-ILDs from the SSc database registry at Srinagarind Hospital, Thailand from 1 January 2012 to 1 October 2018. All patients received monthly oral dosages of CYC 600-750mg/m2, Mesna, and daily prednisolone of 10mg for 2years. Changes of FVC, chest radiography, HRCT, 6MWT, and side effects were recorded for the baseline and at the end of the treatment. Response to treatment was defined by (a) stable FVC or a decline ≤ 10% of predicted, (b) unchanged or improved radiographic findings, or (c) a decline 6MWT of ≤ 30m compared with the baseline. A total of 76 patients with female 52 patients (68.4%) and with a median age of 54.2years (IQR 46.6-59.6). The majority was dcSSc subset (59 patients; 78.6%). Fifty-four patients (71%) were defined as responsive to therapy. The mean FVC improvement was 1ml (SD 9.5). The only factor associated with treatment response was limited cutaneous SSc (OR 7.69, 95% CI (1.01, 339.68), p = 0.029). Hemorrhagic cystitis was found in 1 patient. Nearly three-quarters of SSc-ILDs patients had a good response to the pulse oral CYC therapy for 2years with a few serious side effects. Pulse oral CYC therapy had been effective for SSc-ILDs in case of difficult IV access. Key Point • Pulse oral cyclophosphamide has been used for scleroderma lung disease. It has shown efficacy and safety in scleroderma patients. In patients who have difficulty with intravenous access, pulse oral cyclophosphamide can be an alternative regimen.

The predictive role of lung ultrasound in progression of scleroderma interstitial lung disease.

Lung ultrasound (LUS) correlates with chest high-resolution computed tomography (HRCT) findings in the diagnosis of interstitial lung disease (ILD) in systemic sclerosis (SSc). The aim of this study is to evaluate the predictive value of LUS in the progression of ILD. At baseline, forty-one SSc patients underwent HRCT, LUS for detection of B-lines, and pulmonary function test (PFTs). PFTs were performed also after 12months to evaluate pulmonary function deterioration. In multiple regression analysis, positive correlation exists between the number of B-lines and HRCT score (r = 0.51, p < 0.05), conversely a negative correlation exists between number of B-lines and carbon monoxide diffusing capacity (DLCO) (r = - 0.49, p < 0.05) and FVC (r = - 0.42, p < 0.05). The number of B-lines significantly (p < 0.05) increased with progression of digital microvascular damage. At 12months, a positive correlation exists between number of B-lines and delta of DLCO. The ROC curves demonstrated a good accuracy of worsened DLCO prediction for Delta DLCO (0.72, p < 0.05 95% CI 0.56-0.88). The sum of B-lines correlates with the radiological score evaluated by HRCT. We also demonstrate that the number of B-lines can predict the worsening of the ILD. Although HRCT is the gold standard technique for assessing ILD, the LUS could become a useful tool for guiding the use of HRCT.Key Points• In systemic sclerosis patients, the number of B-lines can predict the worsening of the interstitial lung disease• High-resolution computed tomography of chest is the gold standard technique for assessing interstitial lung disease• Lung ultrasound could become a useful tool for guiding the use of high-resolution computed tomography of chest.

Recent progress in systemic sclerosis-interstitial lung disease.

Systemic sclerosis is a systemic autoimmune disorder wherein interstitial lung disease (ILD) is the major source or morbidity and mortality. Research into mechanisms of fibrosis and its intersection with autoimmunity, specifically lung fibrosis, has accelerated and been applied to autoimmune disorders such as scleroderma. This review highlights important emerging insights and treatment trials. The important elements of this review focus on the challenges faced in identifying patients not only who develop lung disease but who are at a higher risk for progression given the heterogeneous natural history of ILD in scleroderma. Risk assessment scoring models using radiographic and physiologic parameters are highlighted and recent and ongoing clinical trials in scleroderma ILD are discussed. The implications of much of this ongoing work is a potential paradigm shift in our ability to identify those patients at risk for progression, and to offer novel therapies that can limit the progression of inflammatory and fibrotic lung disease in this challenging group of patients.

A COMPARISON OF FVC, FVC/DLCO AND TLC/DLCO AS AN INDICATOR FOR INTERSTITIAL LUNG DISEASE IN PATIENTS WITH SCLERODERMA

SESSION TITLE: Characteristics of Interstitial Lung Disease SESSION TYPE: Original Investigations PRESENTED ON: 10/10/2018 02:30 pm - 03:30 pm PURPOSE: Pulmonary function tests (PFTs) have been reported to be unreliable for the identification of interstitial lung disease (ILD) in Scleroderma patients. A normal Forced Vital Capacity [FVC], was reported in 62.5% of these Scleroderma patients with significant ILD on high resolution CT (HRCT) of chest. The correlation of FVC/DLC and TLC/DLCO to pulmonary fibrosis in Scleroderma patients has not been studied. The objective of this study was to compare the correlation between FVC, Total Lung capacity [TLC] / Diffusion Capacity [DLCO]) ratio and FVC/DLCO ratio, respectively, with the extent of ILD measured by a fibrosis score on HRCT of chest in patients with Scleroderma. METHODS: The records of 40 patients with Scleroderma without Pulmonary Arterial Hypertension followed at the rheumatology clinic our institution were reviewed. Patient demographics and PFT parameters (FVC, TLC, and DLCO) were noted. FVC/DLCO and TLC/DLCO was calculated for each patient. Patients’ chest HRCT scans were graded by a radiologist for ILD by a HRCT Fibrosis Score, calculated by estimating the percentage of parenchymal involvement in three zones (upper, middle, lower) of each lung, with a score of 100 representing normal and a score of 400 representing severe fibrosis. PFT variables were recorded as percent predicted (%) and expressed as mean + SD. Pearson’s test for linear correlation was used to determine correlation of Fibrosis Score with respectively-FVC, FVC/DLCO and TLC/ DLCO. RESULTS: Mean age was 58.8 +/- 12.9 years; 76% were females; 74% had limited disease. Mean FVC: 87.80 +/- 23.52 %; mean TLC: 94 +/-15.9 %; mean DLCO :72.8 +/- 21%; mean FVC/DLC: 0.20 +/- 0.5; mean TLC/DLCO: 0.33 +/- 0.08. Normal FVC was seen in 70%; normal TLC in 85%.; normal DLCO in 32.5%. Mean fibrosis score was:105.2 +/- 11.3 (Range: 100-280). Using Pearson’s correlation analysis, correlation between fibrosis-score and respectively FVC, FVC/DLC and TLC/DLCO was as follows: FVC vs. Fibrosis Score: r= -0.313; p=0.04; FVC/DLCO vs. Fibrosis Score: r= -0.119; p=0.46; TLC/DLCO vs. Fibrosis Score: r=0.06; p =0.69. CONCLUSIONS: ILD in Scleroderma, estimated by the Fibrosis score, correlates significantly with FVC but not with FVC/DLCO and TLC/ DLCO. CLINICAL IMPLICATIONS: Despite prior studies reporting FVC as an unreliable indicator of ILD in Scleroderma, our study shows that FVC has a strong correlation with pulmonary fibrosis in Scleroderma. Further studies are needed to re-evaluate this. DISCLOSURES: No relevant relationships by Debapriya Datta, source=Web Response No relevant relationships by Carol Halasan, source=Web Response No relevant relationships by Sophie Korzan, source=Web Response

Pulmonary Artery Dimensions as a Prognosticator of Transplant-Free Survival in Scleroderma Interstitial Lung Disease.

Systemic sclerosis is a chronic debilitating autoimmune disease characterized by endothelial dysfunction and multi-organ fibrosis. Interstitial lung disease, a common manifestation of SSc, is termed scleroderma-related interstitial lung disease (SSc-ILD) and along with pulmonary hypertension contributes to a majority of deaths in SSc. SSc-ILD patients frequently develop pulmonary hypertension, which prognosticates a poorer outcome. We investigated pulmonary artery dimensions as an outcome predictor in patients with SSc-ILD. A retrospective chart review abstracting data from SSc-ILD patients evaluated at a large tertiary care center was performed. HRCT imaging was reviewed and pulmonary artery (PA) and ascending aorta (Ao) diameters were measured for calculation of the PA:Ao ratio. Additionally, demographics, vital signs, spirometric parameters, comorbidities, and mean pulmonary artery pressures were collected when available. Outcome analysis with lung transplant or death events within 4years based on pulmonary artery size as well as PA:Ao ratio was performed. 70 SSc-ILD patients were identified. Mean pulmonary artery diameter and PA:Ao ratio was 31.17 and 1.07mm, respectively. Patients with a pulmonary artery diameter≥32mm had higher risk of lung transplantation or death (p<0.001) within 4years. Patients with a PA:Ao ratio≥1.1 also had higher risk of lung transplantation or death (p<0.001) within 4years. Unadjusted outcomes analyses also identified PA:Ao ratio≥1.1 as an independent outcome predictor (hazard ratio 3.30, p<0.001). In SSc-ILD patients, a PA:Ao ratio≥1.1 is associated with higher risk of lung transplant or death. These data suggest that PA:Ao dimension may be used for prognostication in SSc-ILD.

Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: a single-centre, retrospective analysis.

BackgroundScleroderma is a systemic autoimmune disease characterized mainly by skin manifestations and involvement of various visceral organs, especially the lungs. Lung involvement is the leading cause of mortality in patients with scleroderma. There are data to suggest that cyclophosphamide (CYC) and mycophenolate mofetil (MMF) are effective in the management of scleroderma interstitial lung disease (SSc-ILD) but no head to head comparative data are available to date.MethodsFor the last 3 years, patients with SSc-ILD have been treated at our centre by protocol-based administration of intravenous CYC and MMF. Results of lung function tests (spirometry) were recorded at baseline, 3 months and 6 months in every patient. The clinical records of patients with systemic sclerosis and significant ILD, who were not previously exposed to any immunosuppressant and were treated with MMF OR CYC, were reviewed. The efficacy of treatment was assessed by the change in forced vital capacity on spirometry.ResultsOf the total 57 patients included in the analysis, 34 were treated with MMF and 23 were treated with CYC. Mean duration of illness was 4.19 ± 2.82 years in the MMF and 6.04 ± 5.96 years in the CYC group. After 6 months of therapy, FVC increased by 10.84 ± 13.81 % in the CYC group and by 6.07 ± 11.92 % in the MMF group. This improvement from baseline was statistically significant in both groups (P < 0.01). The improvement was comparable with no statistically significant differences between groups (P = 0.373). There were no major adverse events reported in either arm.ConclusionBoth MMF and CYC were equally effective in stabilizing lung function in patients with scleroderma and ILD.

Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma.

BackgroundScleroderma is an antigen-driven T cell-mediated autoimmune disease. Presence of anti-topoisomerase-I antibodies is associated with pulmonary fibrosis and predicts increased mortality. Characterization of autoreactive T lymphocytes may shed light on disease pathogenesis and serve as a biomarker for disease activity. Here, we aimed to quantify and functionally characterize circulating topoisomerase I (topo-I)-specific CD4+ T cells and to define their association with presence and progression of interstitial lung disease (ILD) in patients with scleroderma.MethodsUsing flow cytometry, circulating topo-I-reactive CD4+ T cells were identified by the expression of specific activation markers (CD154 and CD69) upon stimulation with purified topo-I and quantified in 27 SSc patients and 4 healthy donors (HD). Polarization of autoreactive T cells (Th1, Th2, Th17, Th1–17) was defined using surface expression of specific chemokine receptors. Presence and progression of ILD were determined using high-resolution chest CT and pulmonary function tests.ResultsTopo-I-reactive CD4+ T cells were found in all topo-I-positive patients compared to one topo-I-negative subject and no HD. Topo-I-specific CD4+ T cells exhibited a distinct Th17 polarized phenotype. Autoreactive T cells were significantly increased in subjects with evidence of ILD and were quantitatively associated with the decline of lung volumes.ConclusionsTopo-I-specific T cells can be reliably quantified in the peripheral blood of patients with scleroderma, exhibit a pro-inflammatory Th17 phenotype, and predict progression of ILD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0993-2) contains supplementary material, which is available to authorized users.

Transitions to different patterns of interstitial lung disease in scleroderma with and without treatment

ObjectivesThe aim is to investigate whether the 12-month quantitative changes in high-resolution CT (HRCT) measures of interstitial lung disease (ILD) are different, and to understand how they change, in patients...

Predictors of lung function decline in scleroderma-related interstitial lung disease based on high-resolution computed tomography: implications for cohort enrichment in systemic sclerosis-associated interstitial lung disease trials.

BackgroundThe extent of lung involvement visualized by high-resolution computed tomography (HRCT) is a predictor of decline in forced vital capacity (FVC) in scleroderma–interstitial lung disease. Our objective was to evaluate the performance of three different HRCT-defined staging systems in the Scleroderma Lung Study I (SLS I) over a 1-year period.MethodsWe assessed two visual semiquantitative scores: the maximum fibrosis score (MaxFib, the fibrosis score in the zone of maximal lung involvement) and visual assessment of total lung involvement (TLI) as proposed by Goh and Wells. In addition, we evaluated the computer-aided diagnosis and calculated the quantitative percentage with fibrosis (QLF) and TLI.ResultsThe mean duration of the disease was 3.2 years, and the mean FVC was 67.7 %. Regardless of the staging system used, a greater degree of fibrosis/TLI on HRCT scans was associated with a greater decline in FVC in the placebo group. Using the MaxFib and QLF, the mean absolute changes in FVC from baseline were 0.1 % and −1.4 %, respectively, in <25 % lung involvement vs. a change of −6.2 % and −6.9 %, respectively, with >25 % involvement (negative score denotes worsening in FVC). Conversely, cyclophosphamide was able to stabilize decline in FVC in subjects with greater degree of involvement detected by HRCT. Using the visual MaxFib and QLF, the mean absolute improvements in FVC were 1.2 and 1.1, respectively, with >25 % involvement.ConclusionsHRCT-defined lung involvement was a predictor of decline in FVC in SLS I. The choice of staging system for cohort enrichment in a clinical trial depends on feasibility.Trial registrationClinicalTrials.gov identifier: NCT00004563 (Scleroderma Lung Study I)ISRCTN15982171. Registered 19 Aug 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0872-2) contains supplementary material, which is available to authorized users.

Efficacy and Safety of Mycophenolate (MMF) Vs Oral Cyclophosphamide (CYC) for Treatment of Scleroderma-Interstitial Lung Disease (Ssc-ILD): Results of Scleroderma Lung Study II

Efficacy and Safety of Mycophenolate (MMF) Vs Oral Cyclophosphamide (CYC) for Treatment of Scleroderma-Interstitial Lung Disease (Ssc-ILD): Results of Scleroderma Lung Study II

The Assessment of Health-Related Quality of Life in Scleroderma-Interstitial Lung Disease

Introduction: Pulmonary involvement is the most common cause of mortality and disability in patients with systemic sclerosis and it significantly affects the quality of life in these patients. Therefore, early diagnosis and treatment of pulmonary involvement seems necessary in patients with SSc. In this study, we aimed to assess the health-related quality of life (HRQoL) in patients with Scleroderma-Interstitial Lung Disease (SSc-ILD) and its relationship with pulmonary function parameters. Materials and Methods: Considering the inclusion and exclusion criteria, 25 patients with SSc-ILD were enrolled in this cross-sectional study from April 2012 to June 2013. Full tests of lung function, including body plethysmography and diffusing capacity of the lungs for carbon monoxide (DLCO), 6-minute walk distance (6MWD), and pulse oximetry were performed. The HRQoL was assessed using St. George’s and CAT questionnaires; also, dyspnea was evaluated for all the patients, using modified medical research council (MMRC) scale. Afterwards, the relationship between the total scores of HRQoL questionnaires and the severity of lung disease was analyzed, based on the recorded variables. Results: The mean age of the patients was 40.36±9.50 years and the mean duration of the disease was 7.16±4.50 years. A statistically significant inverse correlation was observed between 6MWD (r=-0.50, P=0.01), DLCO (r=-0.67, P<0.001), and CAT total score. In addition, there was a statistically significant negative association between CAT score and total lung capacity (r=-0.46, P=0.01). Finally, a significant direct relationship was observed between the total scores of CAT and St. George’s questionnaires (r=0.75, P<0.001). Conclusion: The results of this study showed that CAT questionnaire is a suitable tool for assessing the quality of life in SSc patients; moreover, it is significantly related to the factors associated with pulmonary function. Therefore, the CAT questionnaire may be used to track pulmonary function in SSc patients.

Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease

The interstitial lung diseases (ILD) include a large number of chronic, progressive, irreversible respiratory disorders involving pulmonary fibrosis, the most common of which are idiopathic pulmonary fibrosis and scleroderma lung disease (SSc ILD). Because bleomycin causes lung fibrosis when used in cancer chemotherapy, it is used to model human ILD in rodents. In most studies, bleomycin has been delivered directly into the lung by intratracheal or intraoral administration. Here we have compared the effects in mice of bleomycin delivered directly into the lungs (direct model) or systemically using osmotic minipumps (pump model) to determine which more closely resembles human ILD. The pump model is more similar to human SSc ILD in that: 1) lung injury/fibrosis is limited to the subpleural portion of the lung in the pump model and in SSc ILD, whereas the entire lung is affected in the direct model; 2) conversely, there is massive inflammation throughout the lung in the direct model, whereas inflammation is limited in the pump model and in SSc ILD; 3) hypertrophic type II alveolar epithelial cells are present at high levels in SSc ILD and in the pump model but not in the direct model; and 4) lung fibrosis is accompanied by dermal fibrosis. The pump model is also move convenient and humane than the direct model because there is less weight loss and mortality.

Correlation of Cough With Disease Activity and Treatment With Cyclophosphamide in Scleroderma Interstitial Lung Disease: Findings From the Scleroderma Lung Study

Background Cough is a significant symptom in patients with scleroderma interstitial lung disease (SSc-ILD), affecting 73% of the 158 patients enrolled in the Scleroderma Lung Study (SLS), a multicenter randomized trial of oral cyclophosphamide (CYC) vs placebo (PLA) in patients with active interstitial lung disease. Methods We examined the correlation of cough frequency and severity and phlegm production at baseline in 156 SLS participants with other baseline variables representing SSc-ILD disease activity and the cough response to 1 year of treatment with CYC vs PLA. Results Patients with cough at baseline had significantly lower diffusing capacity of the lung for carbon monoxide, dyspnea, the quality-of-life physical component summary, and the maximal fibrosis score on high-resolution CT imaging compared with those without cough at baseline. Cough severity and frequency correlated with FVC % predicted. After 12 months of treatment, cough frequency decreased in the CYC group compared with the PLA group and was significantly different from the PLA group at 18 months (6 months after discontinuation of CYC). However, the decreases in cough frequency did not correlate with the changes in FVC or diffusing capacity of the lung for carbon monoxide observed in the CYC group. Treatment-related improvements in cough frequency, as well as in FVC, were no longer apparent 12 months after discontinuation of CYC. Conclusions Cough is a common symptom in SSc-ILD and correlates with the extent of fibrosis. Cough frequency decreases significantly in response to treatment with CYC but returns to baseline 1 year after withdrawal of treatment. Cough may be a symptom of ongoing fibrosis and an independent variable in assessing therapeutic response to CYC. Trial registry ClinicalTrials.gov; No.: NCT000004563; URL: www.clinicaltrials.gov Cough is a significant symptom in patients with scleroderma interstitial lung disease (SSc-ILD), affecting 73% of the 158 patients enrolled in the Scleroderma Lung Study (SLS), a multicenter randomized trial of oral cyclophosphamide (CYC) vs placebo (PLA) in patients with active interstitial lung disease. We examined the correlation of cough frequency and severity and phlegm production at baseline in 156 SLS participants with other baseline variables representing SSc-ILD disease activity and the cough response to 1 year of treatment with CYC vs PLA. Patients with cough at baseline had significantly lower diffusing capacity of the lung for carbon monoxide, dyspnea, the quality-of-life physical component summary, and the maximal fibrosis score on high-resolution CT imaging compared with those without cough at baseline. Cough severity and frequency correlated with FVC % predicted. After 12 months of treatment, cough frequency decreased in the CYC group compared with the PLA group and was significantly different from the PLA group at 18 months (6 months after discontinuation of CYC). However, the decreases in cough frequency did not correlate with the changes in FVC or diffusing capacity of the lung for carbon monoxide observed in the CYC group. Treatment-related improvements in cough frequency, as well as in FVC, were no longer apparent 12 months after discontinuation of CYC. Cough is a common symptom in SSc-ILD and correlates with the extent of fibrosis. Cough frequency decreases significantly in response to treatment with CYC but returns to baseline 1 year after withdrawal of treatment. Cough may be a symptom of ongoing fibrosis and an independent variable in assessing therapeutic response to CYC.

Interstitial Lung Disease in Scleroderma: Clinical Features and Pathogenesis

Interstitial lung disease is a prevalent but worrisome implication in scleroderma. It is now the leading cause of morbidity and mortality since the dramatic reduction in death caused by scleroderma renal crisis. However, the pathogenesis remains unknown. Most observers suggest that lung injury induces microvascular damage and immunologically-mediated inflammation. As oxidative stress and leukotrienes-lipoxins imbalance is observed in -ILD patients, a series of proinflammatory and profibrotic cytokines are also found. Possible biomarkers including SP-D, KL-6, Caveolin-1, IL-6, IL-1 may be useful index for diagnosis and progression, which also suggest the potential mechanism. There are also some studies focusing the relationship between gastroesophageal reflux (GER) and SSc- ILD, which partly explain the mechanism from a new perspective.

Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4+ T cells in the broncho-alveolar lavage of patients with systemic sclerosis

T cells, particularly those producing IL-4, are implicated in inflammation-mediated fibrosis. In our phase I/IIa open-label pilot study in 15 patients with scleroderma-interstitial lung disease (SSc-ILD), high-dose imatinib treatment showed modest improvement in lung function and skin score, but with several adverse events. Here, we investigated T cell phenotype and cytokine production in bronchoalveolar lavage (BAL) from patients enrolled in this trial. We found that IL-4(+) T cells showed a stronger correlation with ground glass opacity (GGO) than fibrosis scores on lung high-resolution computer tomography scans. Frequencies of IL-4(+) T cells also discriminated patients with high (≥20) versus low (<20) GGO scores. Functional annotation clustering of proteins that correlated with T cells identified two major clusters that belonged to immune/inflammatory and wounding response. Repeat analyses after 1 year of treatment in 10 BAL samples, one each from the right middle and lower lobes of lung from 5 patients, showed that post-imatinib, IL-4(+) T cells were profoundly reduced but CD4(+) T cells increased, except in one patient who showed worsening of SSc-ILD. Post-imatinib increase in CD4(+) T cells correlated with soluble ICAM-3 and PECAM-1 levels in BAL, which associated with the lack of worsening in SSc-ILD. Thus, imatinib might confer its therapeutic effect in fibrosis via re-directing T cell responses from type 2 to other, non-type 2 cytokine producing CD4(+) T cells.

Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors.

Bronchoalveolar lavage fluid and progression of scleroderma interstitial lung disease

So far no clinical or experimental evidences clearly explain how and which systemic sclerosis (SSc) patients will experience a functional and radiological progression of interstitial lung disease (ILD). The aim of the study was to investigate whether any bronchoalveolar lavage fluid (BALF) characteristic, compared with clinical, functional and radiological parameters, is associated with the risk of progression of ILD and worse survival in SSc patients. Lung involvement was evaluated in 110 consecutively examined SSc patients with pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT); 73 patients with evidence of ILD on HRCT underwent BAL. The progression of ILD was evaluated with PFTs and HRCT after 1-year follow-up. A 36-month survival analysis was assessed. ILD patients with alveolitis had a higher risk to have restrictive lung disease and honeycombing, to experience a worsening in honeycombing score or to develop honeycombing. ILD progression was associated with the evidence of honeycombing on HRCT, with the presence of eosinophils, with an inverted CD4/CD8 ratio and with a higher CD19 percentage count in the BALF or with a positive BALF microbiological culture. The patients with ILD had a worse overall survival. The diffuse disease was the only independent risk factor of overall mortality, and the extent of honeycombing on HRCT was the only independent risk factor of lung disease-related mortality. Our study suggests the importance of evaluating ILD with HRCT and BAL in order to characterize the risk factors of SSc lung involvement progression.