Plasma TGF beta in systemic sclerosis: a cross-sectional study.

OBJECTIVES--To determine whether the active 25 kDa form of the fibrogenic cytokine transforming growth factor beta (TGF beta) can be detected in plasma from patients with systemic sclerosis and to examine the relationship between plasma TGF beta and clinical markers of disease severity and serum concentrations of the aminoterminal peptide of type III procollagen (PIIINP) (a laboratory marker of the fibrotic process). METHODS--A cross sectional study was made of 39 patients with systemic sclerosis (11 diffuse and 28 limited), nine patients with primary Raynaud's disease and 60 healthy controls. TGF beta 1 and TGF beta 2 were measured by enzyme linked immunosorbent assay (ELISA) (sensitivity 100 pg/ml) and PIIINP by radioimmunoassay. RESULTS--TGF beta 1 was detected in plasma from six of 39 patients with systemic sclerosis but not in any patient with primary Raynaud's disease or healthy controls. TGF beta 2 was not detected in plasma from patients or controls. No clear relationship was demonstrated between TGF beta 1, clinical features or PIIINP concentrations. CONCLUSIONS--The 25 kDa form of TGF beta 1 can be detected in the plasma of some patients with systemic sclerosis. This provides limited support for the hypothesis that this cytokine plays a role in the pathogenesis of this disease. However, longitudinal studies, particularly in early diffuse disease, are required to clarify the relationship between circulating TGF beta 1 and disease activity.     

Connective tissue metabolites in serum as markers of disease activity in patients with rheumatoid arthritis

The serum levels of aminoterminal type III procollagen peptide (S-PIIINP), immunoreactive prolyl 4-hydroxylase protein (S-IRPH), 7S domain of collagen type IV (S-Col IV, 7S), and fragment P1 of laminin (S-Lam), which are associated with the metabolism of extracellular interstitial collagens and basement membranes, were measured sequentially for two years in 14 rheumatoid arthritis (RA) patients undergoing disease modifying antirheumatic drug treatment. Elevated S-PIIINP, S-IRPH, and S-Col IV, 7S levels were demonstrated in active RA. In active disease the metabolites showed some correlation with clinical and serological signs of disease activity. A high average synovial fluid/serum concentration ratio of PIIINP and of Col IV, 7S supports the concept that the increased serum levels of PIIINP and Col IV, 7S originated from the diseased joints. After 2 years of treatment a decline was observed in S-PIIINP and S-Col IV, 7S in treatment responders. However, the median levels of S-PIIINP and S-IRPH were still above the upper limit of normal, suggesting smouldering, subclinical inflammatory processes. S-Lam remained within the normal range in active and inactive disease.     

Procollagen type III aminoterminal peptide in serum in idiopathic myelofibrosis and allied conditions: relation to disease activity and effect of chemotherapy

The serum concentration of the aminoterminal propeptide of type III procollagen (PIIINP) was measured serially in patients with idiopathic myelofibrosis and other myeloproliferative syndromes. Two different assays were applied, the RIA-gnost assay (Hoechst, Frankfurt, FRG) and a new equilibrium RIA for the N-terminal propeptide of human type III procollagen (Farmos Diagnostica, Oulu, Finland). A positive correlation was found between the results obtained by the two RIA's (rho = 0.90, P less than 0.001). The highest propeptide levels were recorded in patients with idiopathic myelofibrosis, particularly in those with active disease. Elevated serum PIIINP levels decreased during treatment with various cytotoxic drugs, including intensive chemotherapy. By contrast, serum PIIINP was unchanged or increased in patients undergoing interferon alpha-2b therapy. Gel filtration of sera on Sephacryl S-300 column (Pharmacia, Sweden) showed that smaller PIIINP related peptides dominated in healthy subjects and in osteomyelosclerosis with stable disease. Conversely, the relative proportion of intact propeptide increased in accelerating disease stages and acute myelofibrosis. In conclusion, the present study implicates serum PIIINP as a useful indicator of disease activity in idiopathic myelofibrosis. The propeptide also appears to be a sensitive sero-marker of chemotherapy effect on fibrogenesis related to clonal myeloproliferation. Finally, the propeptide is suggested as an early predictor of relapse during cytotoxic therapy.     

Normal circulating serum amyloid P component concentration in systemic sclerosis

OBJECTIVE: The observation of reduced circulating concentrations of the constitutive plasma pentraxin protein, serum amyloid P component (SAP), in serum samples obtained from a small number of patients with systemic sclerosis (SSc) has been reported as confirmation of an antifibrotic role of this protein. Because neither sustained SAP depletion in humans nor SAP deficiency in mice is associated with fibrosis, we sought to establish rigorously the serum SAP concentration in well-characterized patients with SSc. METHODS: Serum concentrations of SAP were measured by electroimmunoassay in a cross-sectional cohort of 20 patients with diffuse cutaneous SSc and 12 patients with limited cutaneous SSc, and in a separate 12-month longitudinal cohort of 13 patients with diffuse disease and 37 patients with limited disease. The extent and severity of disease were characterized in detail at the time of serum sampling. Serum concentrations of the classic acute-phase reactants, C-reactive protein and serum amyloid A protein, were measured by immunonephelometric assays. RESULTS: SAP values were entirely within the normal range, regardless of the extent and severity of disease, apart from a very few isolated raised values associated with acute intercurrent complications causing major acute-phase responses. CONCLUSION: We observed no reduced circulating concentrations of SAP in patients with SSc, nor any evidence of an association between SAP levels and the extent or severity of fibrosis.     

Serum levels of aminoterminal type III procollagen peptide and hyaluronan predict mortality in systemic sclerosis.

Systemic sclerosis (SSc) is characterized by an excessive accumulation of collagen in skin and internal organs and increased serum concentrations of different connective tissue metabolites have been reported. In this study of 82 patients with SSc, serum concentrations of aminoterminal type III procollagen peptide (PIIINP), smaller PIIINP-related antigens (Fab PIIINP) and hyaluronan (HA) were increased as compared to healthy controls matched for age and sex. Patients with a shorter disease duration (less than 3 years) had higher serum levels of PIIINP and Fab PIIINP than patients with a longer disease duration. The highest serum concentrations of PIIINP and HA were seen in seven patients who died within 2 years.     

Circulating collagen metabolites in systemic sclerosis. Differences between limited and diffuse form and relationship with pulmonary involvement

OBJECTIVE: To study collagen metabolites in systemic sclerosis (SSc) and their relationship with clinical manifestations of the disease. METHODS: Forty-eight SSc patients, 13 with a diffuse form (dcSSc), 23 with a limited form (lcSSc) and 12 with suspected SSc not fulfilling the ACR criteria, and 31 healthy controls were examined. Serum concentrations of aminoterminal type III procollagen peptide (PIIINP), aminoterminal and carboxyterminal type I procollagen peptides (PINP and PICP) and cross-linked carboxyterminal telopeptide of collagen I (ICTP) were determined by radioimmunoassay. RESULTS: Increased serum concentrations of ICTP were found in SSc patients compared with controls. Distinctly higher levels of ICTP were observed in dcSSc than in lcSSc. High serum ICTP was correlated with skin score and acute phase reactants, and with reduced pulmonary function. Serum PIIINP concentration was elevated in both lcSSc and dcSSc. CONCLUSION: Augmented collagen catabolism accompanies the increased collagen synthesis in SSc. Serum ICTP concentration is a marker of this feature and also reflects clinical severity.     

Serum concentrations of soluble P-selectin glycoprotein ligand-1 are increased in patients with systemic sclerosis: association with lower frequency of pulmonary fibrosis

OBJECTIVE: To determine serum concentrations of soluble P-selectin glycoprotein ligand-1 (sPSGL-1) and its clinical associations in patients with systemic sclerosis. METHODS: Serum sPSGL-1 concentrations from 65 patients with systemic sclerosis were examined by enzyme linked immunosorbent assay. In a retrospective longitudinal study, 177 sera from 35 patients with systemic sclerosis were analysed (follow up 0.3 to 6.3 years) RESULTS: Serum sPSGL-1 was raised in patients with limited cutaneous systemic sclerosis (lSSc) (n = 34) and diffuse cutaneous systemic sclerosis (dSSc) (n = 31) compared with healthy controls (n = 22) and patients with systemic lupus erythematosus (n = 20) or dermatomyositis (n = 20). Patients with systemic sclerosis who had raised sPSGL-1 concentrations less often had pulmonary fibrosis and decreased vital capacity (%VC) than those with normal sPSGL-1 levels. sPSGL-1 concentrations were positively correlated with %VC in patients with systemic sclerosis. In the longitudinal study, patients with systemic sclerosis but without pulmonary fibrosis had consistently increased sPSGL-1 concentrations in the early phase, while those with pulmonary fibrosis had decreased sPSGL-1 throughout the follow up period. CONCLUSIONS: A raised serum sPSGL-1 is associated with a lower frequency and severity of pulmonary fibrosis in systemic sclerosis. sPSGL-1 could be a protective factor against the development of pulmonary fibrosis in this disease and as such would be a possible therapeutic target.     

Type III procollagen N-terminal propeptide, soluble interleukin-2 receptor, and von Willebrand factor in systemic sclerosis

OBJECTIVE: To evaluate the blood concentration of type III procollagen N-terminal propeptide (PIIINP), soluble interleukin-2 receptor (sIL-2R), and von Willebrand factor (vWF) in systemic sclerosis (SSc) patients. METHODS: PIIINP, sIL-2R, and vWF were measured in the sera and plasma of 29 SSc patients and 29 sex- and age-matched healthy controls. Serum PIIINP was determined by radioimmunoassay. Both serum sIL-2R and plasma vWF were measured by enzyme-linked immunosorbent assay (ELISA). Associations between concentrations and clinical and laboratory features were evaluated. RESULTS: Serum levels of PIIINP and sIL-2R were significantly higher in the SSc group than in the control group (p < 0.01 for both). No differences in serum PIIINP and sIL-2R levels were found between the limited and diffuse cutaneous subsets. However, PIIINP concentrations were significantly higher in anti-Scl-70 positive SSc patients compared with those of anti-Scl-70 negative patients (p = 0.01). Serum PIIINP levels were significantly higher in SSc patients with restrictive pulmonary function (FVC < 80%) than in patients with normal pulmonary function (p < 0.05). The correlation between PIIINP levels and FVC (p < 0.05) was negative, but the correlation between PIIINP levels and modified Rodnan skin scores (p < 0.05) was positive. sIL-2R levels were not correlated with skin and pulmonary involvement of SSc. There was no difference in vWF levels between those of the SSc patients and those of the control groups. CONCLUSION: These results suggest that serum PIIINP serves as a biologic marker for the extent of skin and pulmonary involvement in systemic sclerosis. Increased serum levels of sIL-2R in SSc patients support a role for T lymphocyte activation in the pathogenesis of systemic sclerosis.     

Is measurement of type III procollagen amino propeptide useful in primary biliary cirrhosis?

We have examined the value of serum type III procollagen amino propeptide (PIIINP) measurement both in evaluation of disease activity and in estimation of prognosis in primary biliary cirrhosis (PBC). 55 paired sera from 32 PBC patients not receiving treatment known to affect PIIINP levels not with non-hepatic inflammatory conditions were used to estimate serum PIIINP by radioimmunoassay. Significant correlations were found between serum PIIINP and serum albumin (P less than 0.001), bilirubin (P less than 0.002) and aspartate transaminase (P = 0.01). The mean serum PIIINP level rose with advancing histological stage (P less than 0.001). In 18 patients in whom more than 1 serum was assayed (mean follow-up 42 months) PIIINP often fell, particularly in patients with established cirrhosis and advanced disease. The independent prognostic value of PIIINP was examined using Cox's proportional hazards model with three other prognostic co-variables (bilirubin, albumin, patient age). Stepwise regression analysis selected albumin (P less than 0.001) and bilirubin (P = 0.002) as the most important prognostic factors. PIIINP did not give independent prognostic information. We conclude that PIIINP is another marker of disease activity in PBC which confers no benefit over existing conventional measurements in routine management of this disease.     

Plasma bilirubin and gamma-glutamyltransferase activity are inversely related in dyslipidemic patients with metabolic syndrome: Relevance to oxidative stress

Background

Subnormal levels of plasma bilirubin levels are associated with premature coronary artery disease and cardiovascular morbidity. Plasma gamma-glutamyltransferase (GGT) activity is linked to bilirubin level in hepatic disease and elevated GGT is equally associated with hepatic steatosis, a frequent feature of metabolic syndrome (MS). In order to assess the potential relationship between GGT activity and bilirubin levels in subjects exhibiting features of the metabolic syndrome, we determined circulating bilirubin levels and GGT activity in a cohort of dyslipidemic patients.

Methods and results

This cross-sectional study involved patients (n = 1433) displaying atherogenic dyslipidemia in primary prevention referred to our Prevention Center. Among these patients, 25% presented with MS as defined by recent NCEP ATP III criteria. Circulating levels of transaminases, as well as GGT activity, were elevated in MS patients; by contrast, bilirubin concentrations were significantly lower in such patients as compared to those lacking this syndrome (p < 10–4 for all comparisons). Comparisons of patient groups on the basis of the number of MS criteria which were concomitantly present revealed a progressive decrease in mean bilirubin levels; this reduction paralleled a progressive increase in mean GGT activity as a function of the number of MS components in the overall population (p value for trend < 10–4).

Conclusion

Elevation in systemic GGT activity, which is characterized by extended generation of ROS, together with potentially deficient bilirubin-mediated antioxidative capacity of plasma, may therefore constitute key components of the systemic oxidative stress typical of metabolic syndrome.     

CARBOXYTERMINAL TYPE I PROCOLLAGEN PEPTIDE CONCENTRATIONS IN SYSTEMIC SCLEROSIS: HIGHER LEVELS IN EARLY DIFFUSE DISEASE

Systemic sclerosis (SSc) is characterized by increased collagendeposition in skin and internal organs, and increased serumconcentrations of different connective tissue metabolites havebeen reported. In this study serum concentrations of carboxyterminaltype I (PICP) and aminoterminal type III procollagen peptide(PIIINP) were higher in 24 patients with diffuse cutaneous systemicsclerosis (dSSc), than in 30 patients with limited cutaneoussystemic sclerosis (lSSc). Thirty patients with advanced andprogressing disease had higher serum concentrations of bothpeptides than 24 patients with milder disease. In patients withadvanced disease, both peptides showed a negative correlationto disease duration. Despite being relatively higher both inearly, widespread and advanced disease, serum PICP concentrationsvaried only within the normal range for healthy controls. ThusPICP is of limited value as a marker of disease activity inSSc. KEY WORDS: Procollagen peptide, Collagen, Aminoterminal type III procollagen peptide, Scleroderma     

Progressive systemic sclerosis with eosinophilia and a fulminating course

A case of progressive systemic sclerosis, with blood and pleural fluid eosinophilia and a fulminating course, is presented. Wide-mouth colonic diverticula developed within 10 weeks. Death from renal failure occurred five and a half months after the onset of symptoms. The possibility of eosinophilia as a marker of severe disease in progressive systemic sclerosis is raised.     

Comparison of assays for N-amino terminal propeptide of type III procollagen in chronic hepatitis C by using receiver operating characteristic analysis.

OBJECTIVE: During the process of liver fibrosis, type III procollagen is converted to type III collagen by cleavage of its amino terminal and carboxy terminal propeptides. Serum levels of amino terminal propeptide of type III procollagen (PIIINP) are a marker of collagen turnover in liver fibrosis. Two assays for PIIINP are available, one which measures both Col 1-3 (collagen synthesis) and Col 1 (collagen degradation) peptides, and one which measures Col 1-3 only. Using receiver operating characteristic analysis, the two PIIINP assays were compared with serum ALT as markers of liver disease in chronic hepatitis C. METHODS: Serum PIIINP was measured using both assays in 33 patients with chronic hepatitis C and five healthy controls. Liver biopsies in chronic hepatitis C patients were scored using a previously described grading and staging system. RESULTS: Serum PIIINP was significantly elevated in chronic hepatitis C compared to controls using both the combined Col 1-3 and Col 1 (median 0.61 vs 0.33 U/ml, P=0.001) and Col 1 assays (median 6.5 vs 3.5 microg/l, P=0.006). Serum PIIINP measured by the combined assay was significantly related to liver fibrosis, periportal necrosis and histological activity index (P<0.05). The area under the curve for specificity and sensitivity in detecting advanced liver disease was only significant for the combined assay (P=0.017). Serum PIIINP measured by the Col 1 assay was not related to these indices of disease severity while serum ALT was only related to portal inflammation. CONCLUSION: A serum PIIINP assay which measures both Col 1-3 and Col 1 peptides instead of Col 1-3 peptide alone is more predictive of severity of liver disease and should be used in preference as a non-invasive marker of liver injury in chronic hepatitis C.     

Application of markers of collagen metabolism in serum and synovial fluid for assessment of disease process in patients with rheumatoid arthritis.

OBJECTIVE--To assess the potential of markers of collagen metabolism to reflect disease processes in rheumatoid arthritis (RA). METHODS--Serum (S) and synovial fluid (SF) from 59 patients with RA, and a knee joint effusion and serum from 90 control subjects were studied with radioimmunoassays for the aminoterminal propeptides of type I and type III procollagens (PINP and PIIINP, respectively). The breakdown of type I collagen was quantified with a radioimmunoassay for the cross linked carboxyterminal telopeptide of type I collagen (ICTP). RESULTS--About 50% of the patients had increased S-ICTP and S-PIIINP values, whereas S-PINP was increased in only 20% of the patients. The mean SF:S ratios of these markers varied between 4 (for ICTP) and 340 (for PIIINP), indicating that markers of collagen metabolism are formed locally and then released into the circulation. SF-PINP and SF-PIIINP correlated with each other (rs = 0.86, p < 0.001) and with SF-ICTP (rs = 0.69, p < 0.001, and rs = 0.65, p < 0.001, respectively). SF-ICTP was clearly related to radiographic findings in the corresponding knee joint, patients with gross bone deformation having the greatest SF-ICTP concentrations. S-ICTP and S-PIIINP also correlated with conventional markers of disease activity, such as C reactive protein and joint swelling score. CONCLUSION--Markers of collagen metabolism both in serum and synovial fluid can be measured to provide an assessment of disease process in patients with RA. ICTP and PIIINP are the most informative.     

Autologous and allogeneic mixed lymphocyte reactions in progressive systemic sclerosis

The autologous and allogeneic mixed lymphocyte reactions (MLR), observed when peripheral blood mononuclear cells from 20 patients with progressive systemic sclerosis were used, were compared with those of age-, sex-, and race-matched normal controls. Such cells were separated by gradient centrifugation of sheep red blood cell (E) rosettes into stimulator (E- or non-T cell) and responder (E + or T cell) populations. The autologous MLR of both the progressive systemic sclerosis and normal peripheral blood mononuclear cells varied widely but there was no statistical difference between the means of each group. In the allogeneic MLR, proliferation between progressive systemic sclerosis non-T cells and normal T cells was significantly less than that of normal non-T cells and progressive systemic sclerosis T cells (P = 0.001). A decreased autologous MLR, while noted with other autoimmune diseases, was lacking in progressive systemic sclerosis. This suggests a different defect. The differences in the allogeneic MLR also suggest that either progressive systemic sclerosis non-T cells were poor stimulators or T cells associated with this disease were better responders when compared with similarly prepared cell populations from normal individuals. The MLR differences could have also resulted from compositional subset alterations or the sharing of a common antigen. HLA-DR5 was found in 9 of the 17 white patients with progressive systemic sclerosis. Although these individuals were evenly distributed as low, medium, and high responders, this finding showed that some progressive systemic sclerosis non-T cells shared a common antigen.     

Serum concentrations of aminoterminal propeptide of type III procollagen and propeptide of human type I procollagen in systemic lupus erythematosus

The purpose of this study was to assess the association between the serum levels of aminoterminal propeptide of type III procollagen (PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) with disease activity and damage in systemic lupus erythematosus (SLE). Thirty-three patients with SLE were compared with 31 controls. The assessment in SLE included disease activity indices (SLEDAI, MEX-SLEDAI) and damage index (SLICC/ACR). PIIINP and PICP were measured by radioimmunoassay. Compared with controls, mean levels of PIIINP were higher in SLE (2.9±1.8 vs. 1.8±1.2, P=0.006). PICP was also increased in SLE versus controls (163±94 vs. 102±62, P=0.007). PIIINP was correlated with SLICC/ACR (r=0.33, P=0.048). No correlation was observed between PICP and PIIINP with other clinical or therapeutic variables. These preliminary data suggests a role of PIIINP as a marker for chronic damage. Follow-up studies are required to evaluate its utility in predicting future damage.     

Serum type III procollagen and basement membrane proteins as noninvasive markers of hepatic pathology in Indian childhood cirrhosis

While serum concentrations of antigens of the aminopropeptide of type III procollagen have been considered as indicators of hepatic pathology in adults, the high concentrations normally found in children during growth may preclude their use in pediatric liver disease. To clarify this and to determine the role of other circulating connective tissue-related substances in children, we have measured serum concentrations of antigens related to aminopropeptide of type III procollagen, the 7S domain of type IV collagen and the P1 fragment of laminin in healthy subjects aged 1 month to 4 years and in children with Indian childhood cirrhosis, a particularly aggressive form of liver disease. In healthy subjects, there was a considerable age variation in serum aminopropeptide of type III procollagen but not in 7S collagen or laminin P1. In Indian childhood cirrhosis, all three serum antigens were increased (p less than 0.001) above the upper limit of normal for age. Both the serum 7S collagen and laminin P1 concentrations showed a significant correlation with the degree of intralobular fibrosis and also with the severity of necrosis and cellular infiltration, suggesting that these serum antigens may be a noninvasive means of assessing and monitoring events associated with hepatic fibrosis in Indian childhood cirrhosis. The raised serum aminopropeptide of type III procollagen in Indian childhood cirrhosis did not correlate with any histological parameter assessed. Gel filtration of serum showed that, in healthy subjects, the predominant antigenic form of aminopropeptide of type III procollagen was a degradation peptide smaller than authentic aminopropeptide of type III procollagen; while in Indian childhood cirrhosis the authentic peptide and a larger degradation peptide predominated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional renal involvement in normotensive patients with progressive systemic sclerosis. impaired sodium excretion during isotonic saline infusion

An intravenous infusion of 2,000 ml isotonic saline was performed in 8 normotensive, normoreninemic patients with progressive systemic sclerosis. None of them had clinical evidence of renal disease. Total and proximal fractional excretion of sodium was reduced when compared with that of 8 normal subjects. No correlation was found with para-aminohippurate (PAH) clearance values. Two years after this study was done, 4 patients developed arterial hypertension; interestingly, plasma renin activity remained within the normal range. Reduced sodium excretion is suggested as having a pathogenetic role in the hypertension of progressive systemic sclerosis.     

Juxtaglomerular hyperplasia and hyperreninemia in progressive systemic sclerosis complicated acute renal failure

The etiology of renal failure in progressive systemic sclerosis remains unexplained. In this patient with progressive systemic sclerosis rapidly progressive azotemia developed resulting in death. Kidney tissue obtained by percutaneous renal biopsy and later at autopsy revealed striking hyperplasia of the juxtaglomerular apparatus. The plasma renin activity measured by bioassay was extremely high. The clinical and morphologic findings in this patient suggest a possible pathophysiologic role for the renin-angiotensin system in the acute renal decompensation that occasionally occurs in progressive systemic sclerosis.     

Effect of antiviral therapy on markers of fibrogenesis in patients with chronic hepatitis C

BACKGROUND: The possible markers of liver fibrosis (plasma YKL-40, PIIINP, MMP-2 and TIMP-1) were measured at the start (t0) and end of treatment (t12) with alpha-interferon and ribavirin and repeated at 6-months follow-up (t18) in 51 patients with chronic hepatitis C. METHODS: We evaluated 1) whether treatment response is reflected by a decrease in these markers during antiviral therapy; 2) whether these markers reflect the activity of the disease; and 3) whether these markers could be used as predictors of the treatment response. RESULTS: Baseline plasma YKL-40, MMP-2, PIIINP and TIMP-1 were significantly increased in patients compared to normal controls. In responders (n = 30), plasma YKL-40 (P < 0.05), MMP-2 (P < 0.05) and TIMP-1 (P < 0.001) decreased significantly at t18, and no changes were observed at t12. Plasma PIIINP was unchanged in responders. In non-responders (n = 19), plasma MMP-2 (P < 0.01) and TIMP-1 (P < 0.01) decreased significantly at t18, whereas plasma YKL-40 and PIIINP were unchanged. The markers were significantly correlated at baseline (P < 0.001). Plasma PIIINP at baseline could predict treatment response (P = 0.01). CONCLUSIONS: Response to antiviral treatment is associated with a decrease in the fibrogenetic markers, but the markers do not reflect the biochemical disease activity during treatment. Baseline plasma PIIINP was the only marker predicting treatment response.