Pulmonary Fibrosis In Systemic Sclerosis Research Articles

State-of-the-art evidence in the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Association of quantitative computed tomography ındices with lung function and extent of pulmonary fibrosis in patients with systemic sclerosis.

The aim was to investigate the discriminative value of a wide range of quantitative computed tomography (qCT) parameters in systemic sclerosis (SSc) patients with and without pulmonary fibrosis (PF) and their association with pulmonary function tests (PFTs) and visual fibrosis scores (VFS). Thoracic high-resolution computed tomography (HRCT) images of SSc patients with and without PF were analyzed with Vitrea® Advanced Visualization software. The mean lung attenuation (MLA), skewness, kurtosis, and threshold-based volumes [low-density volume (LDV), medium-density volume (MDV), and high-density volume (HDV)] derived from the attenuation histograms of the right and left lungs were evaluated separately. Visual scores were measured semi-quantitatively and the overall extent of pulmonary parenchymal abnormality was calculated. Forty-one SSc patients with PF (85.4% female; mean age 50.4 ± 15.6years) were compared with 94 without PF (88.3% female; mean age 50 ± 11.5years). All qCT parameters were significantly different between those with and without PF (p < 0.05). Amongst the qCT measurements, R-MLA, L-MLA, R-MDV, L-MDV, and left total lung volume (L-TLV) correlated with all three of forced vital capacity, carbon monoxide diffusion capacity, and VFS, even after adjustment for sex and age (|r|> 0.300 and p < 0.05). R-MLA, L-MLA, R-HDV/TLV, and L-HDV/TLV exhibited diagnostic accuracy in discriminating patients with PF (AUC value > 0.7). QCT parameters differentiated SSc patients with PF from the ones without and showed a good correlation with VFS. With the application of user-friendly and less operator-dependent software, qCT analysis may become an objective tool for analysis of PF in SSc, complementary to PFTs and VFS. Key Points • Quantitative computed tomography parameters can accurately and objectively differentiate between SSc patients with and without PF. • Furthermore, in SSc patients with fibrosis, a moderate to a high correlation was identified between many of the qCT parameters, PFT results, and VFS.

Laboratory strategy for autoantibodies testing as a diagnostic marker of pulmonary fibrosis in systemic sclerosis: A preliminary study prior to cohort registry of systemic sclerosis in West Java Indonesia

Background: Interstitial lung disease (ILD) is a complication often found in patients with Systemic Sclerosis (SSc). This usually manifests as pulmonary fibrosis and is the leading cause of death in SSc patients. Antinuclear antibodies indirect immunofluorescence (ANA-IIF) test and specific autoantibodies testing could be employed as a diagnostic marker to detect pulmonary fibrosis, but the high cost of these tests often burdens patients in developing countries. This study aims to compare ANA-IIF and an alternative, possibly inexpensive method to detect pulmonary fibrosis in SSc. Methods: This is a preliminary study prior to the cohort systemic sclerosis registry conducted in Rheumatology Outpatient Clinic and Clinical Pathology Department at Dr. Hasan Sadikin General Hospital, Bandung, from January 1, 2018 to December 31, 2020. Two contrastive laboratory testing strategies were followed to confirm pulmonary fibrosis in 61 SSc patients. The first strategy was to perform antinuclear antibodies indirect immunofluorescence (ANA-IIF) test followed by specific autoantibodies detection [anti-topoisomerase-I (ATA), Anti-Th/To, SSc Profile, Immunoblot]. The alternative strategy included conducting the tests for SSc autoantibodies in the reverse order. Results: A total of 42 out of 61 (68.8%) subjects were diagnosed with pulmonary fibrosis by high-resolution computed tomography (HRCT) scan. The first strategy detected dominant specific pulmonary fibrosis autoantibodies in subjects with pulmonary fibrosis: homogeneous nucleolar pattern was dominant (n = 25, 59.52%), followed by nucleolar pattern (n = 17, 40.48%). Of all the subjects with a homogeneous nucleolar pattern, ATA was detected in 15 subjects (60%), the combination of ATA and Th/To in 9 subjects (36%), and Ro52 in one subject (4%). The second strategy yielded positive autoantibodies results in 29 out of 42 (69.05%) subjects, ATA in 20 subjects (47.61%), and Th/To in 9 patients (21.44%), but failed to detect any autoantibodies specific to SSc-ILD in 13 subjects (30.95%). Conclusion: The first strategy [ANA-IIF followed specific autoantibodies testing (ATA, Th/To, SSc profile and immunoblot)] is more likely to detect specific autoantibodies toward ILD in SSc patients.

Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosis.

Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-β-dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH-1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH-1 in SSc by evaluating the clinical correlation between serum VASH-1 levels and the expression of VASH-1 in SSc-involved skin. Serum VASH-1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH-1 as compared to those without. Importantly, serum VASH-1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL-6 levels, but not serum surfactant protein D levels. In SSc-involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH-1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc-like endothelial properties, did not affect VASH-1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH-1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH-1 to SSc vasculopathy seems to be limited.

Asiatic acid prevents the development of interstitial lung disease in a hypochlorous acid-induced mouse model of scleroderma.

Interstitial lung disease is the most common complication of systemic sclerosis (SSc) and is associated with a high rate of mortality. Due to the complex pathogenesis of SSc, the therapies currently available remain limited. In the present study, the effect of asiatic acid (AA) on SSc-associated pulmonary fibrosis (PF) and its association with the transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling pathway were evaluated. A hypochlorous acid (HOCl)-induced model of SSc was used to evaluate the therapeutic effect of AA on PF in SSc, where AA was administered to SSc mice by gavage. PF was alleviated in the AA-treated SSc mice groups when examined under light microscopy. In addition, there was a decrease in histopathological progression and collagen in the lungs. AA significantly reduced expression of type I collagen in the lungs of mice with SSc. It also significantly suppressed α-smooth muscle actin expression, which attenuated the conversion of fibroblasts into muscle fibroblasts. These AA-associated antifibrosis and anti-immune effects were mediated through the significant downregulation of advanced oxidation protein product, E-selectin, and anti-DNA topoisomerase-1 autoantibody levels in the serum. Furthermore, the expression levels of TGF-β1 and the phosphorylated-Smad2/3/Smad2/3 ratios in AA-treated SSc mice were similar to the control. The presence of pulmonary inflammation and fibrosis was confirmed in the HOCl-induced SSc mice and the results demonstrated that selective inhibition of reactive oxygen species prevented PF. By focusing on the classical TGF-β1/Smad2/3 signaling pathway, a mechanism of action of AA was identified to be associated with the inhibition of Smad2/3 activation through negative regulation of Smad2/3 phosphorylation.

The status of pulmonary fibrosis in systemic sclerosis is associated with IRF5, STAT4, IRAK1, and CTGF polymorphisms.

Pulmonary fibrosis (PF) is one of the leading causes of death in systemic sclerosis (SSc) patients. Although all SSc patients are characterized by autoimmunity, only part of them suffer from PF, suggesting that beside autoimmunity, some additional factors are involved in the initiation of PF in SSc. In this study, we aimed to identify genetic polymorphisms associated with the status of PF in SSc. We performed that an exhaustive search of the PubMed database was performed to identify eligible studies. Then, a comprehensive meta-analysis was performed by comparing PF+-SSc and PF--SSc patients to identify genetic polymorphisms associated with the status of PF in SSc. Among eight SSc-associated susceptibility polymorphisms which were applied for meta-analysis, IRF5 rs2004640 polymorphism (OR 1.12; 95% CI 1.02-1.22, P=1.39×10-2), STAT4 rs7574865 polymorphism (OR 1.25; 95% CI 1.07-1.47, P=5.3×10-3), IRAK1 rs1059702 polymorphism (OR 1.20; 95% CI 1.05-1.37, P=0.007), and CTGF G-945C polymorphism (OR 1.42; 95% CI 1.18-1.71, P=0.002) are associated with PF status in SSc, while TNFAIP3 rs5029939, CD226 rs763361, CD247 rs2056626, and IRF5 rs10488631 polymorphisms are not. Since IRF5, STAT4, and IRAK1 are important regulatory factors in the control of innate immune responses and CTGF is involved in the synthesis of extracellular matrix, these results suggest a role of the innate immunity and matrix compounds in the pathogenesis of PF in SSc.

Ultrasound signs of pulmonary fibrosis in systemic sclerosis as timely indicators for chest computed tomography

Objectives: Systemic sclerosis (SSc) patients in the early stages of pulmonary fibrosis (PF) often have few or no symptoms, normal to borderline pulmonary function tests, and negative chest X-ray (CXR); high-resolution computed tomography (HRCT) is the only reliable means of detecting the early signs of PF. However, thoracic ultrasound (TUS) enables detection of pleural thickening, pleural/subpleural nodules, and other subpleural lung abnormalities across 70% of the subpleural surface. We reassessed concordance between TUS abnormalities and HRCT findings in SSc patients, to see whether TUS pleural line thickness (normally < 3.0 mm) could be used to earmark those with asymptomatic PF for timely HRCT assessment.Method: In total, 175 SSc patients (nine males, 166 females), aged 46.46 ± 15.33 years, were given CXR, TUS, HRCT, echocardiography, and pulmonary function tests.Results: In the 26 patients without HRCT signs of PF, pleural line thickness was ≤ 3.0 mm. In diffuse SSc, 97/137 patients showed pleural line thickening (between 3.0 and 5 mm) and subpleural nodules in 32/97; and 35/137 showed major pleural line thickening (≥ 5.0 mm) with nodules, with good concordance with HRCT patterns indicating lung fibrosis severity. HRCT was normal in 5/137, with pleural line thickness ≤ 3.0 mm.Conclusions: TUS imaging of pleural/subpleural structures can detect ultrasonographic signs of initial PF prior to the onset of respiratory symptoms and function test abnormalities and, together with current criteria, could thereby enable exclusion of PF in SSc patients. Indicating some patients for selective referral to HRCT can thereby delay unwarranted procedures, provided that pulmonary function and TUS images are stable.

SAT0326 Validity of Ultrasound in the Assessment of Pulmonary Fibrosis in Systemic Sclerosis: Correlation with High Resolution Computed Tomography, Pulmonary Function Test and Histological Findings

BackgroundPulmonary fibrosis (PF) is a frequent manifestation in systemic sclerosis (SSc). Currently, high resolution computer tomography (HRCT) is the most common imaging technique used in the assessment of PF; however,...

Lung ultrasound imaging usefulness for assessing the severity of pulmonary fibrosis in systemic sclerosis. Relationship with high‐resolution computed tomography and nailfold videocapillaroscopy (LB514)

Thoracic UltraSound (TUS) assesses 70% of the subpleural areas. Systemic sclerosis (SSc) is characterized by collagen thickening of the skin and by early and progressive microcirculatory impairment. SSc microangiopathy, assessed in vivo by x200 magnification nailfold videocapillaroscopy (NVC), evolves from early enlargement of capillaries (giant capillaries) to capillary loss and hemorrhage (active pattern), and finally, to reactive neoangiogenesis, with capillary ramifications (late pattern). We aimed to assess concordance, if any, between TUS abnormalities, in any phase of disease, and High‐Resolution Computed Tomography (HRCT) findings in SSc, concurrently with the association of the NVC with TUS and HRCT patterns. Methods. 175 SSc patients (M 9, F 166), 46.46 ±15.33 years, were studied by chest x‐rays, TUS, HRCT, echocardiography, pulmonary function tests and NVC. Results. Among 38 patients with limited SSc, without respiratory symptoms, normal spirometry, normal diffusing capacity of the lung and 6‐min O2 desaturation walk test, 17/38 show TUS pleural line thickening 蠅3.0 &lt;5 mm with slight posterior‐basal reticular pattern at HRCT, 21/38 have normal pleural thickness (&lt;3 mm) and normal HRCT. In diffuse SSc: 97/137 patients have minor pleural line thickening (蠅3.0 &lt;5 mm), 32/97 with subpleural nodules; 35/137 have major pleural line thickening (蠅5.0 mm), all with traction cysts and nodules; 5/137 with pleural thickness &lt;3.0 mm have a normal HRCT. By HRCT 65/97 with minor pleural thickening have diffuse reticular pattern fibrosis and 32/97 a reticular‐nodular pattern; no honeycombing. Among the 35 patients with major pleural thickening 蠅 5.0 mm, 2/35 patients show a reticular‐nodular pattern and 33/35, show a frank honeycombing pattern; accuracy of TUS at the reliability analysis is high. There is also an incremental severity of NVC patterns associated with greater pulmonary fibrosis severity at HRCT and TUS; nonetheless, NVC is not discriminating among the different HRCT severity of pulmonary fibrosis,being actually a comprehensive clue of disease activity. Conclusion. TUS imaging with its reproducible measures is a promising complementary tool for early detection of structural lung abnormalities allowing to refer patients selectively to HRCT or to delay referral.

Utility of an open-source DICOM viewer software (OsiriX) to assess pulmonary fibrosis in systemic sclerosis: preliminary results

To investigate the utility of an open-source Digital Imaging and Communication in Medicine viewer software-OsiriX-to assess pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc). Chest high-resolution computed tomography (HRCT) examinations obtained from 10 patients with diagnosis of SSc were analysed by two radiologists adopting a standard semiquantitative scoring for PF. Pulmonary involvement was evaluated in three sections (superior, middle and inferior). For the assessment of the extension of PF, the adopted semiquantitative HRCT score ranged from 0 to 3 (0 = absence of PF; 1 = 1-20 % of lung section involvement; 2 = 21-40 % of lung section involvement; 3 = 41-100 % of lung section involvement). Further, a quantitative assessment (i.e. parameters of distribution of lung attenuation such as kurtosis and mean lung attenuation) of PF was independently performed on the same sections by a rheumatologist, independently and blinded to radiologists' scoring, using OsiriX. The results obtained were compared with those of HRCT semiquantitative analysis. Intra-reader reliability of HRCT findings and feasibility of OsiriX quantitative segmentation was recorded. A significant association between the median values of kurtosis by both the quantitative OsiriX assessment and the HRCT semiquantitative analysis was found (p < 0.0001). Moreover, kurtosis correlated significantly with the mean lung attenuation (Spearman's rho = 0.885; p = 0.0001). An excellent intra-reader reliability of HRCT findings among both readers was obtained. A significant difference between the mean time spent on the OsiriX quantitative analysis (mean 1.85 ± SD 1.3 min) and the mean time spent by the radiologist for the HRCT semiquantitative assessment (mean 8.5 ± SD 4.5 min, p < 0.00001) was noted. The study provides the new working hypothesis that OsiriX may be a useful and feasible tool to achieve a quantitative evaluation of PF in SSc patients.

SAT0028 Systemic sclerosis – effects of agonistic auto-antibodies directed against the angiotensin receptor type 1 and the endothelin receptor type a on immune cells

BackgroundAutoimmunity, vasculopathy and fibrosis are features of Systemic Sclerosis (SSc). The functional link between these three pathophysiological components is still missing. Research suggests an involvement of endothelin-1 and angiotensin II,...

SAT0406 Quantification of interstitial pulmonary fibrosis in systemic sclerosis using an open-source dicom viewer software (OSIRIX)

BackgroundInterstitial pulmonary fibrosis (IPF) is a frequent manifestation in patients with systemic sclerosis (SSc). The severity of lung involvement may vary considerably depending on the underlying disease and it can...

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

Objective To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc).Methods Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2–7.2 years).Results Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up.Conclusion Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.

Pulmonary Fibrosis in Systemic Sclerosis

To evaluate the relationship between pulmonary and myocardial fibrosis in patients with systemic sclerosis (SS). Eighteen patients with SS prospectively underwent cardiac magnetic resonance imaging (CMR) and high-resolution computed tomography (HRCT) of the chest. Cardiac biomarkers (N-terminal pro B-type natriuretic peptide) and quality-of-life measures (SF-36 and SS health assessment questionnaires) were assessed. Two readers blinded to other test results evaluated the CMRs in consensus for functional left and right ventricular parameters and for myocardial late enhancement. HRCT images were reviewed at 5 levels and scored for total disease extent, extent of reticulation, proportion of ground-glass opacities (GGO), and coarseness of reticulation. Right ventricular ejection fraction correlated significantly with the percentage of late enhancement of the myocardium (R=0.63, P<0.01), extent of pulmonary fibrosis (R=0.57, P<0.01), and extent of GGO (R=0.53, P<0.05). Significant correlations were also found between the percentage of late enhancement of the myocardium and the extent of overall pulmonary fibrosis (R=0.59, P<0.05) and the extent of the ground-glass subcomponent (R=0.58, P<0.05). N-terminal pro B-type natriuretic peptide correlated significantly with the number of myocardial segments with late enhancement (R=0.64, P<0.05). Stepwise multiple linear regression revealed the extent of pulmonary GGO to be the only independent predictor of the percentage of myocardial enhancement (R2=0.61, P<0.0001). In patients with SS with pulmonary fibrosis on HRCT images, CMR may be a useful test to detect early-stage myocardial fibrosis.

Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis: association with disease severity

To determine serum growth differentiation factor-15 (GDF-15) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum GDF-15 levels were examined by enzyme-linked immunosorbent assay in 61 patients with SSc and 24 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (duration of follow-up 1.2-7.2 years). Serum GDF-15 levels were significantly elevated in SSc patients (1340 ± 910 pg/ml) compared with healthy individuals (213 ± 79 pg/ml; P < 0.001). Among SSc patients, patients with diffuse cutaneous SSc (n = 31) had higher levels of serum GDF-15 (1609 ± 1069 pg/ml) than those with limited cutaneous SSc (n = 30; 1142 ± 646 pg/ml; P < 0.05). SSc patients with high GDF-15 levels (≥1000 pg/ml) had pulmonary fibrosis, decreased vital capacity, and decreased diffusion capacity for carbon monoxide more often than those with low GDF-15 levels (<1000 pg/ml). GDF-15 levels correlated positively with the extent of skin sclerosis and inversely with percentage vital capacity and diffusion capacity for carbon monoxide in patients with SSc. In a longitudinal study, serum GDF-15 levels were generally decreased during the follow-up. Serum GDF-15 levels were increased in patients with SSc and associated with the extent of skin sclerosis and the severity of pulmonary fibrosis. These results suggest that GDF-15 may play a role in the development of cutaneous and pulmonary fibrosis in SSc. Measurement of serum GDF-15 may be useful for risk stratification in early disease stage.

Serum Interleukin 9 Levels Are Increased in Patients with Systemic Sclerosis: Association with Lower Frequency and Severity of Pulmonary Fibrosis

To determine serum interleukin 9 (IL-9) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum IL-9 levels were examined by ELISA in 71 patients with SSc, 15 with systemic lupus erythematosus (SLE), 15 with dermatomyositis (DM), 39 with atopic dermatitis, and 28 healthy individuals. Serum IL-9 levels were significantly elevated in SSc patients (84.6 ± 76.0 pg/ml) compared with healthy individuals (40.4 ± 41.7 pg/ml; p < 0.001), and patients with SLE (50.7 ± 52.0 pg/ml; p < 0.05) or DM (50.6 ± 55.8 pg/ml; p < 0.05) or atopic dermatitis (41.8 ± 38.8 pg/ml; p < 0.001). Among SSc patients, there were no differences in serum IL-9 levels between those with limited cutaneous SSc and those with diffuse cutaneous SSc. Patients with SSc and raised IL-9 levels less often had pulmonary fibrosis and decreased percentage vital capacity than those with normal IL-9 levels. IL-9 levels were positively correlated with percentage vital capacity in patients with SSc. Serum IL-9 level was increased in patients with SSc, and was associated with lower frequency and severity of pulmonary fibrosis in SSc. IL-9 could be a protective factor against the development of pulmonary fibrosis in this disease, and as such would be a possible therapeutic target.

Nuclear β-Catenin Is Increased in Systemic Sclerosis Pulmonary Fibrosis and Promotes Lung Fibroblast Migration and Proliferation

Pulmonary fibrosis is a disease that results in loss of normal lung architecture, but the signaling events that drive tissue destruction are incompletely understood. Wnt/β-catenin signaling is important in normal lung development, but whether abnormal signaling occurs in lung fibrosis due to systemic sclerosis and the consequences of β-catenin signaling toward the fibrogenic phenotype remain poorly defined. In this study, we show nuclear β-catenin accumulation in fibroblastic foci from lungs of patients with systemic sclerosis-associated advanced pulmonary fibrosis. Forced activation of β-catenin signaling in three independently derived sources of normal human lung fibroblasts promotes proliferation and migratory activities but is not sufficient to activate classic markers of fibroblast activation, such as TGF-β, type 1 collagen, α-smooth muscle actin, and connective tissue growth factor. These findings indicate that activation of β-catenin signaling in pulmonary fibroblasts may be a common feature of lung fibrosis, contributing to fibroproliferative and migratory activities associated with the disease.

Use of Serum Clara Cell 16-kDa (CC16) Levels as a Potential Indicator of Active Pulmonary Fibrosis in Systemic Sclerosis

To clarify the clinical significance of concentrations of serum Clara cell 16-kDa protein (CC16; previously denoted CC10) in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc); and to compare CC16 levels with levels of the current most reliable serum markers for PF, such as Krebs von den Lungen-6 (KL-6) antigen and surfactant protein-D (SP-D). Serum levels of CC16, KL-6, and SP-D were determined by ELISA in 92 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), and 20 healthy controls. In a retrospective longitudinal study, correlation of serum CC16 levels with the activity of PF was assessed in 16 SSc patients with PF. Although CC16 levels were higher in patients with SSc than in SLE patients or healthy controls, the difference was not significant. Increased serum CC16 levels were associated with involvement of PF, especially active PF, as well as KL-6 and SP-D. Receiver operating characteristic curve analysis revealed that the utility of CC16 is slightly inferior to KL-6, but was comparable with that of SP-D for detecting PF in patients with SSc. In the longitudinal study, serum levels of CC16, KL-6, and SP-D were significantly decreased in the inactive disease phase compared to the active disease phase. CC16 levels can be used as a potential serum biomarker for PF in addition to KL-6 and SP-D in patients with SSc.

Pathogenesis of Pulmonary Fibrosis in Systemic Sclerosis: Lessons from Interstitial Lung Disease

Interstitial lung disease is a frequent complication of systemic sclerosis and currently is the leading cause of death. Our ability to predict which individuals are at greatest risk of developing clinically significant, progressive interstitial lung disease remains inadequate. Identification of circulating autoantibodies and other biomarkers, as well as genetic polymorphisms and aberrant gene expression, all hold promise as diagnostic and prognostic tools, as well as therapeutic targets. Many practice patterns for the diagnosis and monitoring of connective tissue disease-associated interstitial lung disease are based upon published experience with idiopathic interstitial lung diseases. Although there are likely commonalities in the pathophysiologic mechanisms and clinical progression among all fibrosing lung diseases, a better understanding of features unique to systemic sclerosis-associated interstitial lung disease is essential to the development of more effective monitoring and treatment strategies.

Proteome Analysis of Bronchoalveolar Lavage Fluid in Lung Fibrosis Associated with Systemic Sclerosis

Interstitial lung disease (ILD) is the major cause of mortality in collagen vascular diseases. However, its pathogenesis still needs to be elucidated. To evaluate the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) and clarify the causative role in the processes of ILD in systemic sclerosis (SSc), we compared a BALF protein profile between 5 patients with systemic sclerosis with pulmonary fibrosis (SSc-fib+) and 4 patients with systemic sclerosis without pulmonary fibrosis (SSc-fib-) using two-dimensional gel electrophoresis (2-DE), and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). We analyzed spots over the range of 10.1kDa to 207.4kDa. SSc-fib+ patients showed increased 3 proteins compared to SSc-fib- including α2-macroglobulin, α1-antitrypsin, and pulmonary surfactant protein A and decreased 2 proteins including α2 heat shock protein (HSP) and glutathione S-transferase (GST) compared to SSc-fib- patients. In conclusion, we identified several interesting proteins that might have roles in ILD of SSc patients. Further studies are warranted to clarify the role of these proteins in the processes of pulmonary fibrosis in SSc.