Comprehensive investigation of novel serum markers of pulmonary fibrosis associated with systemic sclerosis and dermato/polymyositis.

OBJECTIVE To investigate the association between serum levels and clinical signs of lung fibrosis in patients with systemic sclerosis and inflammatory myopathies. METHODS ELISA tests for a mucin-like glycoprotein KL-6, von Willebrandt factor (vWF), soluble E-selectin (sES) and surfactant protein D (SP-D) were performed in sera of 104 patients with systemic sclerosis, 31 patients with poly/dermatomyositis) and 24 patients with Raynaud's phenomenon as controls. The clinical and laboratory data were evaluated by a simple standard protocol including chest x-ray, lung function tests, echocardiography and, in selected cases, high resolution computer tomography (HRCT). Clinically significant pulmonary fibrosis (PF) defined as a simultaneous presence of radiological sign of pulmonary fibrosis and restrictive impairment. Severe PF was established if HRCT scans showed diffuse interstitial lung disease with low diffusing capacity. End stage PF was determined as severe PF with very low diffusing capacity. RESULTS Patients with pulmonary fibrosis on chest x-ray showed significantly elevated serum levels of KL-6, SP-D and vWF. Inverse correlation was found between serum levels of KL-6/SP-D and lung function parameters, such as DLCO% and FVC. With regard to HRCT findings, patients with elevated serum level of KL-6 showed significantly more frequently ground glass opacity, diffuse and honeycombing fibrosis than patients with normal level of KL-6. The sensitivity of KL-6 for PF in SSc is increased with the severity of PF (PF on chest x-ray < severe PF < end stage of PF). Lung fibrosis occurred more frequently in patients with simultaneously elevated KL-6 and sES compared to cases with a single positivity of either KL-6 or sES. CONCLUSION KL-6, SP-D, vWF and ES are good surrogate factors of pulmonary fibrosis but can not replace conventional diagnostic procedures. However, these markers are suitable for the assessment of progression and severity of pulmonary fibrosis in systemic autoimmune disorders once the diagnosis is established.

[1]  T. Medsger,et al.  Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. , 1988, The Journal of rheumatology.

[2]  E. Juhász,et al.  Subclinical pulmonary involvement assessed by bronchoalveolar lavage in patients with early undifferentiated connective tissue disease. , 2001, Clinical and experimental rheumatology.

[3]  N. Kohno,et al.  Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. , 2002, American journal of respiratory and critical care medicine.

[4]  M. Cerinic,et al.  Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. , 2003, Seminars in arthritis and rheumatism.

[5]  Y. Asano,et al.  Clinical and laboratory features of scleroderma patients with pulmonary hypertension. , 2000, Rheumatology.

[6]  K. Yamane,et al.  Serum KL-6 in adult patients with polymyositis and dermatomyositis. , 2000, Rheumatology.

[7]  G. Kinikli,et al.  Serum‐Soluble Selectin Levels in Patients with Rheumatoid Arthritis and Systemic Sclerosis , 2004, Scandinavian journal of immunology.

[8]  K. Kinoshita,et al.  Role of endothelial damage in the pathogenesis of interstitial pneumonitis in patients with polymyositis and dermatomyositis. , 2006, The Journal of rheumatology.

[9]  L. Czirják,et al.  Simultaneous presence of neutrophil alveolitis and Ki-67 positivity of alveolar macrophages in dermato-/polymyositis and systemic sclerosis , 2002, Rheumatology International.

[10]  Y. Aoyama,et al.  Surfactant Protein D (SP‐D) and Systemic Scleroderma (SSc) , 2001, The Journal of dermatology.

[11]  L. Czirják,et al.  Increased urinary pyridinoline cross-link compounds of collagen in patients with systemic sclerosis and Raynaud's phenomenon. , 2001, Rheumatology.

[12]  A. Bohan,et al.  Polymyositis and dermatomyositis (second of two parts). , 1975 .

[13]  L. Czirják,et al.  Predictors of survival in 171 patients with systemic sclerosis (scleroderma) , 1997, Clinical Rheumatology.

[14]  A. Persson,et al.  Surfactant protein D is a divalent cation-dependent carbohydrate-binding protein. , 1990, The Journal of biological chemistry.

[15]  N. Kamatani,et al.  KL-6 as a novel serum marker for interstitial pneumonia associated with collagen diseases. , 2000, The Journal of rheumatology.

[16]  N. Kohno,et al.  KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. , 1997, American journal of respiratory cell and molecular biology.

[17]  M. Fujimoto,et al.  Longitudinal analysis of serum KL-6 levels in patients with systemic sclerosis: association with the activity of pulmonary fibrosis. , 2003, Clinical and experimental rheumatology.

[18]  H. Ihn,et al.  Serum levels of KL-6 as a useful marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. , 2000, The Journal of rheumatology.

[19]  T. Medsger,et al.  Raynaud's phenomenon: a proposal for classification. , 1992, Clinical and experimental rheumatology.

[20]  F. Wollheim,et al.  Inverse relation between plasma concentration of von Willebrand factor and CrEDTA clearance in systemic sclerosis. , 1994, The Journal of rheumatology.

[21]  M. Sakatani,et al.  [KL-6 in patients with interstitial pneumonitis]. , 1996, Nihon Kyobu Shikkan Gakkai zasshi.

[22]  M. Fujimoto,et al.  Clinical significance of surfactant protein D as a serum marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. , 2001, Arthritis and rheumatism.