ANCA-Positive Patients: The Influence of PR3 and MPO Antibodies on Survival Rate and The Association with Clinical and Laboratory Characteristics.

OBJECTIVES: To compare the survival rate, and the clinical and laboratory characteristics in patients, characterized by the presence of certain anti-neutrophil cytoplasmic auto-antibodies (ANCAs). METHODS: In a retrospective observational study, we analyzed the data of all patients with a positive ANCA test between 1995 and 2005 at our hospital. Based on serology patients were divided in three subgroups (ANCA-Proteinase 3 (PR3), ANCA-Myeloperoxidase (MPO) and atypical ANCA), irrespective of the diagnosis. Patient survival was compared by Kaplan Meier survival analysis. Differences in clinical and laboratory characteristics between the groups of specific ANCAs were determined. RESULTS: Fifty-four ANCA-positive patients were analyzed. Eighteen of these patients were ANCA-PR3-positive, 17 were ANCA-MPO-positive and 19 had a atypical ANCA. A random control group was created of matched ANCA negative patients. Average follow-up time was 52 months. The calculated five year survival rate in respectively the ANCA-PR3- positive group, the ANCA-MPO-positive group, the atypical ANCA group and the ANCA-negative group was 45%, 81%, 90% and 100%. (P = 0.012, Wilcoxon test). A higher mean leukocyte count, a higher mean erythrocyte sedimentation rate and more fever was observed in the ANCA-PR3-positive group compared to the ANCA-MPO-positive group. CONCLUSIONS: A remarkable lower survival rate was observed in ANCA-PR3-positive patients compared to ANCA-MPO-positive patients. We also demonstrated that patients characterized by the presence of a defined ANCA differ in clinical and laboratory characteristics.

Churg-Strauss Syndrome following PTU Treatment.

Propylthiouracil (PTU) is a frequently prescribed drug in the treatment of hyperthyroidism. The use of PTU is, however, accompanied by numerous potentially serious side effects including vasculitis. PTU-related vasculitides can present as haematuria, pulmonary haemorrhage, or cutaneous lesion together with aspecific symptoms such as fever, myalgia, arthralgia, and fatigue. Cerebral involvement is seldom observed. We present a 49-year-old female with Graves' disease and asthma, who developed paresis of the proximal extremities, eosinophilia, pulmonary, and cutaneous lesions following treatment with PTU. A cerebral vasculitis consistent with Churg-Strauss syndrome (CSS) was suspected. Although cerebral involvement is seldom observed with PTU treatment, cerebral vasculitis should be considered in patients developing CNS symptoms.

[ANCA(antineutrophil cytoplasmic antibodies)-associated vasculitis in a man with extreme fatigue, fever and progressive renal dysfunction]. / Vasculitis geassocieerd met antineutrofielencytoplasmatische antistoffen (ANCA) bij een man met ernstige vermoeidheid, koorts en een progressieve nierfunctiestoornis.

A 55-year-old man, with no previous history, presented with extreme fatigue and fever and was admitted to hospital. He had progressive renal dysfunction and his serum anti-neutrophil cytoplasmic antibodies (ANCA) were markedly elevated. Renal histology was consistent with ANCA-associated vasculitis. The patient was successfully treated with cyclophosphamide and prednisolone. The classification and management of the ANCA-associated vasculitides are described. The classification was guided by the clinical presentation, serology and results of tissue biopsies. The ANCA inflammation had affected the middle sized and small vessels of especially the upper and lower airways, and the kidneys. The antibodies were directed at proteinase-3 (PR3) or myeloperoxidase (MPO). PR3-ANCA is predominantly found in Wegener's granulomatosis, while MPO-ANCA is related to microscopic polyangiitis. Tissue studies showed granulomatous inflammation of the airways which is typical of Wegener's disease. This type of inflammation is absent in microscopic polyangiitis. The initial treatment schedule consists of prednisone 1 mg/kg daily and oral cyclophosphamide 2 mg/kg daily. In the remission phase, the cyclophosphamide is replaced by azathioprine. It is not yet known how long maintenance treatment should be continued and which parameters have prognostic value.

[Progressive multifocal leukoencephalopathy in a patient following long-term immunosuppressive therapy for systemic lupus erythematosus]. / Progressieve multifocale leuko-encefalopathie bij een patiënte na langdurige immunosuppressieve behandeling wegens lupus erythematodes disseminatus (SLE).

A 41-year-old woman who had suffered from systemic lupus erythematosus (SLE) for 22 years presented with signs of neurological deficits. CT-scanning of the brain revealed hypodense lesions that suggested cerebral infarction due to vasculitis in SLE. However, in spite of intensified immunosuppressive therapy, she showed rapid neurological deterioration. After extensive, additional examinations and tests, the diagnosis was finally changed to progressive multifocal leukoencephalopathy, caused by an opportunistic infection by the JC polyomavirus. Neurological and psychiatric symptoms frequently occur in patients with SLE. The differential diagnosis of these symptoms in SLE is extensive and includes, on the one hand, primary neurological and psychiatric diseases related to direct involvement of the nervous system by SLE, and on the other hand, secondary syndromes arising as a result of complications of the SLE or the immunosuppressive treatment. Opportunistic infections are often an important secondary cause of neurological and psychiatric syndromes in patients with SLE. The clinical symptoms and radiological cerebral signs are non-specific and usually do not suffice to differentiate between the various syndromes. Since each syndrome requires its own specific clinical approach and treatment, extensive diagnostics are mandatory before the diagnosis 'cerebral lupus' can be made and immunosuppressive therapy can be started or intensified.

Profiles of the acute-phase reactants C-reactive protein and ferritin related to the disease course of patients with systemic lupus erythematosus.

OBJECTIVE: To obtain insight in the acute-phase response in SLE. METHODS: The clinical history, SLEDAI, CRP and ferritin concentrations were analysed throughout the disease course of 10 SLE patients. RESULTS: During a mean follow-up of 4.8 years, 10 exacerbations (SLEDAI > or = 11) occurred. Throughout the disease course, CRP and SLEDAI correlated positively in 5 patients, whereas the correlation between SLEDAI and ferritin was positive in 7 patients. However, elevated CRP concentrations together with elevated ferritin levels were only observed during 4 exacerbations. Ferritin concentrations were exceptionately high (> 1500 microg/L) during 4 flare-ups. CRP and ferritin levels remained normal during 5 exacerbations. CONCLUSION: SLE is characterised by highly variable and unusual CRP and ferritin responses that do not always reflect the extent of inflammation in individual patients. Despite severe disease activity, ferritin levels can remain well within the normal range, limiting its clinical usefulness as a marker for disease activity.

A prospective study on silicone breast implants and the silicone-related symptom complex.

This cohort study prospectively evaluated the prevalence of the silicone-related symptom complex (SRSC) in relation to antinuclear antibodies (ANA) and magnetic resonance imaging (MRI) of silicone breast implants (SBI) 1 year after implantation. A total of 57 women undergoing mastectomy followed by immediate breast reconstruction (IBR) and SBI between March 1995 and March 1997 at the University Hospital Rotterdam/Daniel den Hoed Cancer Centre, were prospectively evaluated. Just before and 1 year after IBR the sera of these women were tested for the presence of ANA and they were screened for the prevalence of SRSC-related symptoms by questionnaire. All prostheses were evaluated by MRI 1 month and 1 year after IBR. Just before operation 11% of the women had a Sjögren score of more than 2, whereas 30% had such a score 1 year after IBR ( P = 0.01). One year postoperatively women had significantly more RA/Raynaud-related complaints: 21% preoperatively versus 40% 1 year after IBR ( P = 0.03). Within the undefined complaints-related group 19% had a score of 2 or more preoperatively and 33% 1 year after IBR ( P = 0.09). There were no new cases of ANA positivity 1 year after IBR. The linguine sign was seen by MRI in three implants: one 1 month after IBR and two 1 year after IBR. There was no relation to changes in SRSC expression and these MRI findings. In conclusion, 1 year after SBI implantation women had more SRSC-related complaints, especially Sjögren's and RA/Raynaud's. Moreover there was no correlation between elevated SRSC expression and changes in the presence of ANA or changes in MRI of the SBI 1 year after IBR.

[Clinical thinking and decision making in practice. A young woman with fever, arthralgia and exanthema]. / Klinisch denken en beslissen in de praktijk. Een jonge vrouw met koorts, artralgie en exantheem.

A 19-year-old woman was admitted because of high fever, rash, arthralgia and sore throat. On physical examination a diffuse skin rash was observed, leaving a facial mask unaffected. C-reactive protein and erythrocyte sedimentation rate were raised (114 mg/l and 26 mm in the first hour, respectively); white blood cell count was normal (6.2 x 10(9)/l) with an increased count of immature forms. An infective, metabolic or haematological cause was excluded. Serum ferritin turned out to be extremely elevated (4318 micrograms/l), so adult-onset Still's disease was diagnosed. The patient fulfilled the criteria of Cush et al. for adult-onset Still's disease. She was first treated with non-steroidal anti-inflammatory drugs (NSAIDs) and, at a later stage in the disease, with corticosteroids. All symptoms disappeared and blood test results normalised.

Regulation of ferritin: a specific role for interferon-alpha (IFN-alpha)? The acute phase response in patients treated with IFN-alpha-2b.

BACKGROUND: Adult onset of Still's disease is characterized by very high serum ferritin levels, in disproportion with other acute phase proteins (APPs). Because interferon-alpha (IFN-alpha) was observed to cause hyperferritinaemia in three healthy people without increase of other APPs, we hypothesized that IFN-alpha stimulates specifically the synthesis of ferritin. To test this hypothesis, we studied ferritin and other APP levels in patients treated with IFN-alpha. PATIENTS AND METHODS: Fifteen patients treated with IFN-alpha-2b 3-5 times a week, as adjuvant treatment after excision of a high-risk melanoma, were compared with six patients without adjuvant treatment (controls). Serum levels of C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using ELISA. Levels of ferritin, alpha1-acid glycoprotein (AAG) and albumin were determined by nephelometry. RESULTS: CRP was decreased significantly after 4 weeks (P < 0.01) in the patients treated with IFN-alpha compared with the nontreated patients, after 6 months of treatment it was still decreased although not significantly. Ferritin increased significantly in the IFN-alpha-treated patients: 187% of pretreatment value after 4 weeks and 217% after 6 months (P < 0.01), while ferritin levels decreased in the nontreated patients. AAG increased significantly in IFN-alpha-treated patients (107, 114%) compared with the control-patients (91, 76%) but differences were less compared with CRP and ferritin. sPLA2 had a variable course, while albumin remained constant within the normal range in both patient groups. CONCLUSIONS: IFN-alpha induced a significant increase in ferritin, with a significant decrease in CRP, little increase in AAG, varying response of sPLA2 and no change in albumin. This finding suggests a specific role for IFN-alpha in the synthesis or secretion of ferritin. This mechanism may also be involved in the marked hyperferritinaemia in adult onset of Still's disease.

Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation.

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. At this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10 y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of 1 y. Serious clinical signs or exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished.

Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT).

OBJECTIVE: Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE. METHODS: Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up. RESULTS: Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE. CONCLUSIONS: A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

Systemic toxicity and cytokine/acute phase protein levels in patients after isolated limb perfusion with tumor necrosis factor-alpha complicated by high leakage.

BACKGROUND: Since the introduction of high-dose tumor necrosis factor-alpha (TNFalpha) in the setting of isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient is monitored with great precision for fear of TNF-mediated toxicity. That we observed remarkably little toxicity in patients with and without leakage prompted us to determine patterns of cytokines and acute phase proteins in patients with high leakage and in patients without any leakage. METHODS: TNFalpha, interleukin (IL)-6, IL-8, C-reactive protein, and secretory (s)-phospholipase A2 were measured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to the systemic circulation varying in percentage from 12% to 65%. As a control, the same measurements, both in peripheral blood and in perfusate, were performed in nine patients without systemic leakage. RESULTS: In patients with systemic leakage, levels of TNFalpha increased during ILP, reaching values to 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared with patients without systemic leakage. C-reactive protein and s-phospholipase A2 peaked at day 1 in both patient groups, s-phospholipase A2 with significant higher levels and C-reactive protein, in contrast, with lower levels in the leakage patients. CONCLUSIONS: High leakage of TNFalpha to the systemic circulation, caused by a complicated ILP, led to 10-fold to more than 100-fold increased levels of TNFalpha, IL-6, and IL-8 in comparison with patients without leakage. The increase of the acute phase proteins was limited. Even when high leakage occurs, this procedure should not lead to fatal complications. The most prominent clinical toxicity was hypotension (grade III in four patients), which was easily corrected. No pulmonary or renal toxicity was observed in any patient. It is our experience that, even in the rare event of significant leakage during a TNFa-based ILP, postoperative toxicity is usually mild and can be easily managed by the use of fluid and, in some cases, vasopressors.

[Diagnostic significance of antinuclear antibodies]. / De klinische betekenis van het aantonen van antikernantistoffen.

In three patients, women of 17, 25 and 15 years, suffering from arthralgia and in whom the existence of antinuclear antibodies (ANA) was established, the diagnosis 'systemic lupus erythematosus' was made or considered. Upon reevaluation, the ANA results could not be confirmed. The conclusion was drawn that in patients, who lack one or more clinical signs of a connective tissue disease (CTD), no indication is present for determination of ANA. Literature data indicate that the positive predictive value of ANA for the presence of CTD is 5-10%. Conversely, a negative ANA result does not rule out that CTD is present (negative predictive value: 98.5-99.3%). In addition, the question is raised if a hospital laboratory, lacking experience or routine in ANA assays could reliably perform these assays.

Intrapleural administration of tumour necrosis factor-alpha (TNFalpha) in patients with mesothelioma: cytokine patterns and acute-phase protein response.

BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has been found to be very effective in the isolated limb perfusion setting for advanced extremity tumours. In a phase I study of intrapleural administration of TNFalpha 5 patients were followed for inflammatory response patterns. PATIENTS AND METHODS: Malignant mesothelioma patients were treated with repeated intrapleural administration of 0. 1-0.2 mg recombinant TNFalpha. Samples of serum and pleural fluid were taken at different time-points before and after TNFalpha-administration. Levels of TNFalpha, interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using enzyme-linked immunosorbent assays (ELISAs). Alpha 1-acid glycoprotein (alpha1-AG) was measured by nephelometry. RESULTS: In pleural fluid TNFalpha and IL-8 reached peak levels, up to 50-700 ng mL-1 and 6-60 ng mL-1, respectively, 24 h after administration of TNFalpha. IL-6 (peak levels up to 250 ng mL-1) and sPLA2 peaked after 48 h. A slower and less dramatic pattern was observed for the levels of CRP and alpha1-AG. In serum no detectable levels of TNFalpha and no IL-8 were observed, whereas serum levels of IL-6, sPLA2 and CRP showed a clear increase after intrapleural administration of TNFalpha. Cytokines and acute-phase proteins showed the same pattern during subsequent cycles even up to 12 cycles. Tumour regression was not observed. CONCLUSIONS: In the setting of a phase I study of repetitive intrapleural administration of TNFalpha in mesothelioma patients, we studied the characteristics of the inflammatory response. Intrapleural administration was followed by a clear inflammatory response locoregionally. In spite of TNFalpha peak levels as high as 700 ng mL-1 systemic levels were never detectable. The secondary cytokine response led to very high intrapleural IL-6 and IL-8 levels. Systemically IL-8 levels were never detectable whereas high IL-6 levels were induced systemically initially, with a decreased response to each intrapleural TNFalpha administration over time. The acute-phase response in contrast remained remarkably constant throughout the course of repeated intrapleural administrations of TNFalpha. Intrapleural administration of TNFalpha is well tolerated but associated with inconsistent and rather moderate impact on production of pleural fluid. This can be achieved by other simpler and cheaper treatment, thus we see no justification for further studies.

Histone-containing immune complexes are to a large extent responsible for anti-dsDNA reactivity in the Farr assay of active SLE patients.

Increased titres of anti-dsDNA antibodies, especially if of high avidity, are associated with renal exacerbations in patients with systemic lupus erythematosus (SLE). One of the most reliable assays to measure anti-dsDNA antibodies, the Farr assay, is believed to detect preferentially high avidity antibodies. Purified non-complexed monoclonal antibodies (mAbs) against nucleosomes, obtained from mice with SLE, are not reactive in the Farr assay, but can become so once complexed to nucleosomes. These Farr-positive, nucleosome containing, immune complexes were also able to bind in vivo to the glomerular basement membrane (GBM), predominantly via heparan sulphate (HS). To evaluate whether in SLE patients the same kind of immune complexes are responsible for Farr reactivity, IgG from serum or plasma was isolated under dissociating and physiological conditions. We observed that after purification under dissociating conditions, Farr reactivity was significantly decreased (P<0.0001) in contrast to reactivity with histones and two 'control' antigens: Epstein Barr Virus (EBV) and Ro/SS-A. Reactivity with nucleosomes also decreased after purification, although to a lesser extent. Plasma purified under physiological conditions showed no decrease in Farr reactivity. The importance of histones for the generation of immune complexes is supported by the two following observations. Firstly, the presence of histones could be demonstrated in serum and plasma of SLE patients but not in serum of healthy controls or in IgG preparations purified under dissociating conditions. Secondly, Farr reactivity of purified IgG preparations could be restored by addition of purified histones. From these studies we conclude that histones containing immune complexes are responsible for a large part of the Farr reactivity in active SLE, and are therefore indirectly implicated in the pathogenesis of lupus nephritis.

First evaluation study of the Dutch Working Party on silicone breast implants (SBI) and the silicone-related symptom complex (SRSC).

This cohort study evaluates the postoperative prevalence of antinuclear antibodies (ANA) in relation to symptoms related to the so-called silicone-related symptom complex (SRSC). A total of 63 women who underwent mastectomy followed by immediate breast reconstruction with a silicone implant (SBI) between Septembber 1990 and May 1995 at the University Hospital Rotterdam/Daniel den Hoed Cancer Center, participated voluntarily in the study. Their sera were tested for the presence of antinuclear antibodies (ANA) and at the same time they were screened for the prevalence of SRSC-related symptoms by questionnaire. All patients were also examined physically. Sixteen per cent of the women were ANA positive. There was no difference in SRSC expression between ANA-positive and ANA-negative women. The lack of difference in symptom expression between the ANA-positive and ANA-negative women and the rather low complaint percentage proves that if ANA positivity is related to the SRSC, we found no evidence that patients with a SBI with a positive ANA differed from the ANA-negative patients.

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (

Recombinant human erythropoietin improves health-related quality of life in patients with rheumatoid arthritis and anaemia of chronic disease; utility measures correlate strongly with disease activity measures.

Treatment with recombinant human erythropoietin (r-hu-Epo) in patients with rheumatoid arthritis (RA) and anaemia of chronic disease (ACD) resulted in improvement of both anaemia and disease activity. Utilities represent a generic and comprehensive quality of life measure, capable of integrating domain-specific information into one overall value which a patient assigns to his state of health. Therefore, the effect of r-hu-Epo on quality of life was studied by measuring utilities, derived from the rating scale and standard gamble, in a 52-week placebo-controlled randomised double-blind study with r-hu-Epo in 70 patients with active RA and ACD. Furthermore, the relation between anaemia as assessed by haemoglobin levels (Hb), disease activity as assessed with the Disease Activity Score (DAS), and utilities was investigated. Compared to the placebo group, significant improvement of Hb (P < 0.001), DAS (P = 0.01) and rating scale utilities (P = 0.002), but not of standard gamble utilities, was observed in the Epo group. Rating scale utilities correlated strongly with DAS (r = -0.47, P < 0.01), Hb (r = 0.37, P < 0.01) and changes in both DAS (r = -0.74, P < 0.01) and Hb (r = 0.44, P < 0.01). Both DAS and Hb contributed significantly to the variance in rating scale utilities (21% and 3% respectively) and to changes in rating scale utilities (43% and 3% respectively). Standard gamble utilities correlated less well with clinical disease variables than rating scale utilities did. These results indicate, that r-hu-Epo improves utility-derived health-related quality of life, most probably by improving both disease activity and anaemia. Utilities, particularly rating scale utilities, correlated well with conventional disease activity variables and proved sensitive to change. Utilities may be a useful tool for investigating quality of life in RA-patients.

Acute-phase response patterns in isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan in patients with colorectal liver metastases.

BACKGROUND: In this study, we have evaluated hepatotoxicity, secondary cytokine production and hepatic acute-phase response (APR) in patients who underwent isolated hepatic perfusion (IHP) with tumour necrosis factor (TNF) alpha and melphalan for irresectable colorectal liver metastases. DESIGN: An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. Inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter in the inferior caval vein. The liver was perfused for 60 min with 0.4 mg of TNF-alpha plus 1 mg kg-1 melphalan (IHPTM group, n = 6) or 1 mg kg-1 melphalan (IHPM group, n = 3). The liver was washed with macrodex before restoring vascular continuity. RESULTS: After the washout procedure, a TNF-alpha peak (169 +/- 38 pg mL-1) was demonstrated in the IHPTM group only. Both groups demonstrated peak levels of interleukin 6 (IL-6) in the perfusate as well as systemically. These were significantly higher in the IHPTM group. Acute-phase protein (APP) levels followed a similar pattern as has been demonstrated after major surgery, with no significant differences between both groups. The addition of TNF-alpha to the perfusate did not lead to a significant difference in APP levels and the time course between groups. CONCLUSIONS: IHP with TNF and melphalan is followed by a transient systemic peak of TNF directly after liver washout. Secondary IL-6 induction was seen in the present study after IHP with and without TNF, which was highest when TNF was added. This phenomenon cannot be extrapolated to APP induction, which appeared unaffected by the addition of TNF, presumably because the surgical procedure itself already causes maximal stimulation of APP production.