Elevated sputum BPIFB1 levels in smokers with chronic obstructive pulmonary disease: a longitudinal study.

A previous study involving a proteomic screen of induced sputum from smokers and patients with chronic obstructive pulmonary disease (COPD) demonstrated elevated levels of bactericidal/permeability-increasing fold-containing protein B1 (BPIFB1). The aim of the present study was to further evaluate the association of sputum BPIFB1 levels with smoking and longitudinal changes in lung function in smokers with COPD. Sputum BPIFB1 was characterized by two-dimensional gel electrophoresis and mass spectrometry. The expression of BPIFB1 in COPD was investigated by immunoblotting and immunohistochemistry using sputum and lung tissue samples. BPIFB1 levels were also assessed in induced sputum from nonsmokers (n = 31), smokers (n = 169), and patients with COPD (n = 52) via an ELISA-based method. The longitudinal changes in lung function during the 4-year follow-up period were compared with the baseline sputum BPIFB1 levels. In lung tissue samples, BPIFB1 was localized to regions of goblet cell metaplasia. Secreted and glycosylated BPIFB1 was significantly elevated in the sputum of patients with COPD compared with that of smokers and nonsmokers. Sputum BPIFB1 levels correlated with pack-years and lung function as measured by forced expiratory volume in 1 s (FEV1) % predicted and FEV1/FVC (forced vital capacity) at baseline and after the 4-year follow-up in all participants. The changes in lung function over 4 years were significantly associated with BPIFB1 levels in current smokers with COPD. In conclusion, higher sputum concentrations of BPIFB1 were associated with changes of lung function over time, especially in current smokers with COPD. BPIFB1 may be involved in the pathogenesis of smoking-related lung diseases.

Variant mannose-binding lectin 2 genotype is a risk factor for reactive systemic amyloidosis in rheumatoid arthritis.

OBJECTIVE: The aim of this study was to investigate whether polymorphism of the mannose-binding lectin 2 (MBL2) gene is related to the occurrence of systemic AA amyloidosis in patients with rheumatoid arthritis (RA). METHODS: MBL2 structural gene polymorphisms at codon 52 (CGT-->TGT, Arg-->Cys; D), codon 54 (GGC-->GAC, Gly-->Asp; B) and codon 57 (GGA-->GAA, Gly--> Glu; C), and MBL2 promoter region polymorphism at position -221 (G-->C) were examined in 57 patients with RA complicated by biopsy-proven reactive amyloidosis and 51 control RA patients without amyloid. RESULTS: A strong association was found between the presence of a structural MBL2 gene variant O (B, D or C) and the occurrence of amyloidosis in RA patients: 29 of 57 (50.9%) of the RA patients with amyloid had a variant allele compared with 12 of 51 (23.5%) of the RA patients without amyloid (OR 3.37, 95% CI 1.47-7.72; P = 0.004). CONCLUSION: We conclude that variant MBL2 structural genotype constitutes a significant risk factor for reactive amyloidosis in RA and that the increased risk is probably related to MBL-mediated impairment of mononuclear phagocyte function.

Serum TRACP 5b and ICTP as markers of bone metastases in breast cancer.

BACKGROUND: The purpose of this cross-sectional study was to evaluate the value of serum tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptide of type I collagen (ICTP) separately and in combination as markers of bone metastases compared to total alkaline phosphatase (tALP) in breast cancer. MATERIALS AND METHODS: Two groups of patients were studied, one with verfied bone metastases (N=46) and one without bone metastases (N=141). Bone marker levels were correlated with the presence or absence of bone metastases. RESULTS: Serum TRACP 5b concentrations exhibited the largest area under the receiver-operating characteristics (ROC) curve (AUC=0.845), followed by ICTP (0.818) and tALP (0.814) when all patients were included in the analysis. With the combination of TRACP 5b and ICTP, the AUC increased to 0.881. In multivariate regression analysis, all three markers were significant predictors of bone metastases. CONCLUSION: Serum TRACP 5b, ICTP and tALP exhibited equal performances in the detection of bone metastases. The combination of TRACP with ICTP did not significantly improve the detection of bone metastases over tALP.

Survival markers related to bone metastases in prostate cancer.

Prognostic value of a bone resorption marker, tartrate-resistant acid phosphatase isoform 5b (TRACP 5b), and two matrix metalloproteinases (MMP-2 and MMP-9) was compared with the standard clinical analyses of total alkaline phosphatase (tALP) and prostate-specific antigen (PSA), in prostate cancer (PC) patients with (BM+) or without (BM-) bone metastases. Diagnostic accuracy evaluation showed the highest area under the curve for tALP (AUC=0.98), followed by PSA (AUC=0.87), TRACP 5b (AUC=0.82), MMP-9 (AUC=0.62) and MMP-2 (AUC=0.53). Significantly shorter survival was observed for patients with tALP (p<0.001), TRACP 5b (p=0.002) and PSA (p<0.001) levels, above the determined cut-off values compared with lower marker levels. In multivariate Cox regression analysis, only tALP and PSA, in addition to Gleason score were independent prognostic factors for survival. Of the three novel markers tested, only TRACP 5b proved to be predictive of survival in PC with bone metastases. MMP-2 and -9 are thus not recommended for further studies in this context.

Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of skeletal changes in prostate cancer.

Skeletal metastases are a significant problem in prostate cancer (PC). The patients are also exposed to treatment-related skeletal changes. This cross-sectional study evaluated a marker of bone resorption, TRACP 5b in relation to the standard analyte total alkaline phosphatase (tALP) as a marker of skeletal changes. Serum levels of TRACP 5b, tALP and PSA were measured in 130 prostate cancer patients. Comparison was made between patients with (BM+, n = 25) and without (BM-, n = 105) skeletal metastases, and between those treated with (n = 64) or without (n = 66) androgen deprivation (AD). Sensitivities and specificities were calculated for each marker and diagnostic accuracy was evaluated by ROC curve analysis. ROC curves indicated the superior accuracy of tALP, whereas TRACP 5b and PSA were comparable. With tALP the best combination of sensitivity (96%) and specificity of (91%) was reached at a cut-off point 224 U/L, the corresponding values were for TRACP 5b sensitivity (76%), specificity (89%) with a cut-off point 4.89 U/L, and for PSA sensitivity (65%), specificity (81%) at 23 ng/L for skeletal metastases. Patients treated with AD showed with increasing duration an increase in TRACP 5b values. TRACP 5b was less specific than tALP as a marker of skeletal metastases. TRACP 5b may have a role in the diagnostics of skeletal changes in PC with a focus on treatment-related skeletal changes.

Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interleukin-1beta and interleukin-18.

OBJECTIVE: In amyloid A (AA) amyloidosis the receptor for advanced glycation end products is a target for the circulating amyloid precursor protein (SAA) resulting in upregulation of the proinflammatory cytokine pathway. Besides inducing hepatic SAA synthesis the interleukin-1 cytokine family is involved in the regulation of haematopoiesis. We therefore studied the relationship between the circulating levels of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18), a new member of the IL-1 complex, as well as polymorphisms within the IL-1 cluster with the occurrence of anaemia in patients with AA amyloidosis. DESIGN, SETTING AND SUBJECTS: The study included 54 adult patients with biopsy-proven reactive amyloidosis allocated into three groups on the basis of haemoglobin (Hb) level: group I included all patients with Hb < 110 g L(-1) (n = 16); group II patients (Hb > 110 g L(-1), n = 16) were selected to match group I patients with respect to sex, age, underlying disease (seropositive, erosive rheumatoid arthritis) and renal function; and group III patients (n = 38) represented all patients (unselected) with Hb > or = 110 g L(-1). Gene polymorphisms were studied by polymerase chain reaction restriction length assay and included the base exchange at position-889 of the IL-1alpha gene, the polymorphic region at position-511 and the polymorphic locus at exon 5, position +3954 of the IL-1beta gene, as well as the IL-1 receptor antagonist (IL-1Ra) exon 2 polymorphism caused by the 86-bp tandem repeats. Plasma IL-1beta, IL-1alpha, IL-18, IL-1 Ra, SAA, ferritin, soluble transferrin receptor and erythropoietin levels were studied by enzyme immunoassays. RESULTS: Circulating IL-beta and IL-18 were significantly raised in the anaemic patients with AA amyloidosis when compared with group II patients (matched, Hb > 110 g L(-1)) as well as group III patients (nonmatched, Hb > or = 110 g L(-1)). A significant inverse relationship was found between IL-1beta and haemoglobin levels, as well as between IL-18 and haemoglobin levels. The frequency of allele 2 (T) of the IL-1beta-511 promoter gene was significantly increased and that of allele 1 (C) decreased in anaemic amyloid patients (group I) when compared with group II and III patients. Circulating IL-1beta levels tended to be higher amongst the IL-1beta-511 allele 2 carriers than amongst the noncarriers, as well as amongst the anaemic amyloid patients filling all criteria of anaemia of chronic disease. CONCLUSION: The occurrence of anaemia in patients with AA amyloidosis is associated with allele 2 (T) of the IL-1beta-511 promoter gene and elevated levels of circulating IL-1beta and IL-18. In AA amyloidosis the raised cytokine levels may generate a vicious cycle leading to accelerated amyloidogenesis, suppression of erythropoiesis and aggravation of the underlying inflammatory disorder.

Tumor necrosis factor alpha, its soluble receptor I, and -308 gene promoter polymorphism in patients with rheumatoid arthritis with or without amyloidosis: implications for the pathogenesis of nephropathy and anemia of chronic disease in reactive amyloidosis.

OBJECTIVE: To study tumor necrosis factor alpha (TNFalpha) -308 gene promoter polymorphism and circulating levels of TNFalpha and soluble TNF receptor type I (sTNFRI) in rheumatoid arthritis (RA) patients with and without reactive amyloidosis. METHODS: In a retrospective study, we examined 55 RA patients with biopsy-proven reactive amyloidosis and 55 control RA patients without amyloidosis (matched for age, sex, rheumatoid factor titer, and RA duration). Inflammatory activity was assessed by measuring the erythrocyte sedimentation rate and C-reactive protein level. TNFalpha gene promoter polymorphism was studied using polymerase chain reaction-restriction fragment length polymorphism assay. Cytokine and receptor levels were measured by enzyme-linked immunoassays. RESULTS: Patients with RA and amyloidosis had significantly higher TNFalpha and sTNFRI levels than did the control RA patients. The increased circulating levels of TNFalpha correlated with interleukin-18 levels, but not with the serum amyloid A protein levels or with TNFalpha -308 gene promoter polymorphism (reported to be associated with high TNFalpha levels and certain disease susceptibilities). In the patients with RA and amyloidosis, those with anemia had significantly higher TNFalpha and sTNFRI levels than did those without anemia, and circulating TNFalpha and sTNFRI levels correlated negatively with hemoglobin concentrations. In the patients with RA and amyloidosis, those with nephropathy had significantly higher TNFalpha and sTNFRI levels than did those without nephropathy; in patients with isolated proteinuria (but no creatinine elevation) the TNFalpha level was also significantly increased, indicating that the TNFalpha elevation was not merely a consequence of impaired renal function. CONCLUSION: This study shows that circulating levels of TNFalpha and sTNFRI are significantly increased in RA patients with amyloidosis as compared with control RA patients without amyloidosis and that the increased levels may be implicated in the pathogenesis of certain disease manifestations, including anemia of chronic disease and renal pathology in reactive amyloidosis.

Raised circulating interleukin-18 levels in reactive AA-amyloidosis.

OBJECTIVE: To study the circulating levels of interleukin-18 (IL-18), a proinflammtory cytokine implicated in the T helper I response, in patients with rheumatoid arthrtitis (RA) with or without amyloidosis. METHODS: Plasma IL-18 levels were studied by enzyme-linked immusorbent assay in 55 RA patients with reactive amyloidosis and in 55 RA patients without amyloidosis matched with respect to age, sex, seropositivity, disease duration and inflammatory activity, as well as in 55 healthy control subjects. RESULTS: Plasma IL-18 levels were significantly elevated in RA patients as compared with control subjects. Those RA patients who had amyloid had significantly higher circulating level of IL-18 than those without amyloid (418.1 +/- 32.1 ng/l versus 317.0 +/- 21.3 ng/l, P<0.02). This difference was not due to differences in inflammatory activity, nor was it related to renalfunction. CONCLUSION: RA is associated with increased levels of plasma IL-18, the levels being significantly higher in patients with amyloid than in those without amyloid The increased level in the amyloidosis patients may reflect the interaction ofamyloid with cellular meatbolic pathways or, possibly, suggest a direct role of IL-18 in amyloidogenesis.

Apolipoprotein E phenotypes in rheumatoid arthritis with or without amyloidosis.

The role of apolipoprotein (apo) E in the pathogenesis of reactive amyloidosis is unclear. Here we evaluated the apoE phenotype distribution and apolipoprotein e allele frequencies in 55 adult patients with seropositive, erosive RA with amyloid and compared them with 55 matched RA patients without amyloid The apoE isotypes were determined by isoelectric focusing and immunoblotting. RA patients without amyloid had more often the apoE 3/3 phenotype (71%) than the RA+A patients (49%, P<0.05) or Finnish control subjects (47%, P<0.01) and the frequency of the apo epsilon3 allele was significantly higher among the RA patients without amyloid than among RA+A patients (P<0.05) or control subjects (P<0.01). The prevalence of the apoE3/4 phenotype among the RA+A patients, although higher, did not significantly differ from the RA patients without amyloid (40% and 26%, respectively, NS) or Finnish control subjects (40% and 35%, respectively, NS). The frequency of the apo epsilon4 allele among the RA+A patients did not signficantly differ from that of RA patients without amyloid (0.23 and 0.13, respectively, NS) or Finnish control subjects (both 0.23). However, the apo epsilon4 frequency of 0.13 among the RA patients without amyloid was significantly lower than that of Finnish control subjects (0.23, P<0.05). We conclude that the prevalence of the apoE4 isotype is not increased in patients with RA complicated by amyloidosis when compared with Finnish control subjects. Since the frequency of the apo epsilon4 allele is significantly decreased in RA patients without amyloid when compared with Finnish control subjects, the presence of the apoE4 in a patient with RA could, though, represent a relative risk factor for developing reactive amyloidosis.

Secondary amyloidosis has decreased in patients with inflammatory joint disease in Finland.

We studied whether the high incidence of secondary amyloidosis (SA) is a consistent finding in patients with inflammatory joint disease. A total of 4508 biopsies of patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis were studied at the Rheumatism Foundation Hospital during 1987-1997. The results show that the annual number of findings of SA was reduced from 68 to less than 10. We suggest that a change in medication towards more frequent use of cytostatic agents is the reason for the reduction in incidence of SA.

Serum C-reactive protein is rarely lost into urine in patients with secondary amyloidosis and proteinuria.

We studied whether the low serum C-reactive protein (S-CRP) level in patients with inflammatory arthritis and proteinuria was due to the loss of CRP into urine. In 19 patients with secondary amyloidosis (14 with rheumatoid arthritis and five with juvenile chronic arthritis), S-CRP was measured with both immunoturbidimetric and radioimmunoassays. The concentration of urinary CRP was measured with a double-antibody radioimmunoassay. One patient with the most extensive proteinuria (12 g/24 h) excreted CRP at 14 mg/24 h, while in 18 of 19 patients only negligible, if any, amounts of CRP were found in 24-h urine samples. Proteinuria of < 8 g/24 h did not reduce the S-CRP level. Proteinuria exceeding this level may result in increased excretion of CRP into urine and consequently may result in a reduced S-CRP level.

[Does the basic therapy affect the development of secondary amyloidosis in rheumatoid arthritis?]. / Vliiaet li terapiia bazisnogo riada na razvitie vtorichnogo amiloidoza pri revmatoidnom artrite?

Anti-rheumatic drug treatments were studied in 260 patients from Finland and Russia suffering from rheumatoid arthritis (RA) with or without biopsy-proven secondary amyloidosis (RSA). Chloroquine was used for longer period in RSA group in Russia (p = 0.003) and in Finland (p = 0.06). In Finland chloroquine was used more often in the RSA group (p = 0.02), and sulphasalazine (p = 0.02), D-penicillamine (p = 0.03) and cytotoxics (p = 0.04) in the control group. The role of therapy in the prevention of RSA in chronic inflammation is discussed.

Amyloidosis--incidence and early risk factors in patients with rheumatoid arthritis.

In a 15-year follow-up examination, reactive secondary amyloidosis (RSA) was found by subcutaneous fat biopsy in six out of 74 still living patients (8.1%) of an original population of 102 with erosive and seropositive rheumatoid arthritis (RA). Five of the 24 deceased patients had had RSA. Thus the 15-year incidence of RSA in RA was at least 10.9% (11/102). To study early prognostic aspects of RSA, comparison was made of 14 entry variables and the initial treatment in the RSA group (n = 11) and the control group (n = 81) respectively. At onset (< or = 6 months) of RA only serum orosomucoid, but after three years morning stiffness, ESR, serum CRP and orosomucoid were significantly worse in patients whom later developed RSA. Three out of 48 patients treated with gold sodium thiomalate and seven out of 30 treated with chloroquine developed RSA (p = 0.04). It is concluded that continuously active disease was the risk factor underlying RSA. The role of early chloroquine therapy is discussed.

HLA typing and seropositivity in Finnish and in Polish patients with rheumatoid arthritis and amyloidosis.

We determined HLA-A, -B, -C and -DR antigens in 83 patients with rheumatoid arthritis (RA) and reactive secondary amyloidosis (RSA), 60 in Finland and 23 in Poland, and compared the results with control RA patients and blood donors. There were no significant differences in the frequencies of HLA between the RA patients with and those without RSA in either Finland or Poland, and no significant differences between the Finnish and Polish patients with RSA. All the RSA patients from Finland and 70% of the RSA patients from Poland were seropositive. In the development of RSA, the prolonged period of inflammatory stimuli may play a more important role than genetic factors.

Antibodies to arthritis-associated microbes in inflammatory joint diseases.

IgM, IgG and IgA class antibodies against Yersinia, Salmonella, Campylobacter and Borrelia were determined by enzyme-linked immunosorbent assay (ELISA) in a group of 340 unselected patients with a recent inflammatory joint disease. The control group consisted of 340 and 100 healthy blood donors using Borrelia-ELISA and other ELISAs, respectively. Of all the patients, 27.4% had increased antibody levels against at least one of the microbes tested. The prevalence of positive antibody levels was highest in Yersinia antibodies (17.9%). The corresponding figures for Salmonella, Campylobacter and Borrelia were 7.0, 6.2 and 1.8%, respectively. Patients with entero-arthritis or clinically typical reactive arthritis who had not had gastrointestinal or urogenital symptoms previously had the highest prevalence of the microbial antibodies (67.6 and 40.7%, respectively). These findings indicate that arthritis may often have a reactive etiopathogenesis without recognized gastrointestinal infection, emphasizing the importance of microbial serology in the differential diagnosis.

Effect of nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid.

The effect of 9 nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid was studied in patients with normal renal function. Diflunisal, Azapropazone and Indomethacin caused an increase and Piroxicam a decrease in the uric acid excretion. Other drugs studied had no significant influence.

Long-term prognosis of monoarthritis. A follow-up study.

During 1973-75, a total of 446 patients with recent arthritis were examined. The diagnosis in 32 cases was non-classified monoarthritis. After the 3-9 years' follow-up of these 32 patients, two seropositive, definite rheumatoid arthritis cases (6%), and one ankylosing spondylitis case were noted. In the remaining patients the diagnosis was still non-specific arthritis. Of the 31 patients tested, 39% were HLA-B27-positive. The difference between this and the HLA-B27-positivity in the normal Finnish population (14%) is statistically significant (p less than 0.005). At the end of the follow-up the good prognosis of monoarthritis was confirmed: only one erosion developed in one patient's hands or feet.