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Activated protein C (APC), an endogenous anticoagulant, has antithrombotic, fibrinolytic and anti-inflammatory properties. We recently conducted a controlled study (APCAP, activated protein C in severe acute pancreatitis) of APC treatment of patients with severe acute pancreatitis (SAP). Here we studied the effect of APC on the pivotal coagulation parameters of the surviving patients in the APCAP study.The study consisted of 20 patients of whom 10 patients had received APC and 10 patients had received placebo. Coagulation parameters, physiological anticoagulants, thrombograms and circulating levels of IL-6 and CRP were determined on admission and at days 1, 3-4 and 6-7.During follow-up, the temporal levels of prothrombin time (PT) decreased and the temporal levels of thromboplastin time (TT) increased in placebo group (p0.001 for both), but not in APC group. The temporal levels of antithrombin (AT) increased less in APC group than in placebo group (p = 0.011). The shapes of the SAP patients' thrombograms were strongly deranged and were marginally affected by APC treatment.Coagulopathy in SAP, a complex phenomenon, is not alleviated by APC treatment. Rather, the patients receiving APC are heading toward normal homeostasis of coagulation slower than patients receiving placebo.

Reactive arthritis (ReA) is a sterile joint inflammation triggered by a remote infection and associated with human leucocyte antigen (HLA)-B27. Its pathogenesis is unknown, but abnormal response to microbial structures or endogenous inflammatory mediators may be involved. We studied responses in leucocyte signalling profiles in patients with previous ReA after a full recovery.The study comprised 10 HLA-B27-positive healthy subjects with a history of Yersinia enterocolitica-triggered ReA (B27+ReA+) and 20 healthy reference subjects, of whom 10 carried HLA-B27 (B27+ReA-) and 10 did not (B27-ReA-). Phosphospecific fluorescent monoclonal antibodies and flow cytometry were used to determine activation of nuclear factor kappa B (NF-κB), signal transducers and activators of transcription (STATs) 1, 3, 5, and 6, and two mitogen-activated protein (MAP) kinases, p38 and extracellular signal-regulated kinase (ERK)1/2, in monocytes, lymphocytes, lymphocyte subsets, and neutrophils. B27+ReA+ and B27-ReA- whole-blood samples were incubated with Yersinia with or without infliximab to study the role of tumour necrosis factor (TNF) in lymphocyte subset activation. Samples of the three subject groups were studied using soluble bacterial or endogenous stimuli. Fluorescence levels were determined as relative fluorescence units (RFU) and the proportion of positively fluorescing cells.The intracellular activation of circulating leucocytes in response to soluble stimuli was consistently comparable in B27+ReA+, B27+ReA-, and B27-ReA- subjects. Infliximab inhibited Yersinia-induced lymphocyte NF-κB phosphorylation similarly in B27+ReA+ and B27-ReA- groups.ReA susceptibility is not reflected in leucocyte signalling profiles elicited by phlogistic stimuli. However, the possibility remains that aberrations occur in response to combinations of stimuli, such as those associated with leucocyte adhesion.

Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory disease caused by heterozygous mutations in the TNFRSF1A gene encoding for the TNF receptor 1 (TNFR1). TRAPS is a multi-faceted and heterogeneous disease which commonly manifests as recurrent episodes of high fever accompanied by abdominal pain, pleurisy, migratory rash, and myalgia. Disease attacks occur spontaneously or may be elicited by minor triggers. Because of a vigorous and sustained acute-phase response it may be complicated by systemic AA amyloidosis. Therapeutically interleukin-1 blockade seems even more promising than TNF blockade. Studies on the pathogenesis of TRAPS have shown TNFα-dependent cellular signalling to be defective, an enigmatic finding considering the hyperinflammatory phenotype of the disease. Several studies indicate that most mutated receptors never reach the cell surface but are misfolded and trapped in the endoplasmic reticulum, where they may elicit an intracellular inflammatory response, and thus lead to constitutional expression of proinflammatory cytokines. The aim of this review is to describe the current understanding of the pathogenesis of TRAPS by integrating recent clinical and laboratory data.

Complement activation occurs in patients with acute pancreatitis (AP) and may contribute to the development of organ failure. Because a number of enzymes are released during AP that could influence the complement inhibitor CD59, the purpose of this study was to examine serum levels of CD59 in relation to severity of AP.Twelve patients with severe AP had organ failure (referred to as the grade 2 group). For each of them, we found 2-3 age-matched AP patients who served as controls (n=27). Of these, a total of 13 had mild AP (grade 0 group) and 14 severe AP without organ failure (grade 1 group). Blood samples were collected at admission and on days 1 and 3-7 post-admission. Grade 2 patients were compared with grade 0 and grade 1 patients. CD59 levels were measured by a sandwich enzyme immunoassay.At admission, median CD59 levels were significantly higher (p = 0.002) in grade 2 patients (median 104.2 ng/ml, range 26.1-186.3) than in grade 0 patients (37.3, range 30.3-75.9) and grade 1 patients (38.6, range 19.9 96.1). CD59 levels remained higher in grade 2 patients than in grade 0 and 1 patients on day 1 (p = 0.001) and days 3-7 (p = 0.002). The CD59 levels correlated significantly (p0.05) with C-reactive protein (CRP) levels (R = 0.40) and APACHE II scores (R = 0.32) on admission.Organ failure and severity of AP are associated with elevated serum levels of CD59.

Monocyte membrane CD14 (mCD14) and soluble CD14 (sCD14) both associate with poor outcome in sepsis. Because the value of combined use of the markers is unknown we measured both in patients with severe community acquired infections. The study comprised 142 acutely ill patients with community acquired pneumonia and/or blood culture-positive sepsis. Expression of mCD14 was measured, on admission to hospital, by whole blood flow cytometry and sCD14 by ELISA. There was no significant correlation between mCD14 and sCD14. Patients in the lowest tertile of mCD14 were 9.79 times (95% CI 1.31- >50, p =0.006) more likely to die than patients in the middle/highest tertiles. Survival rates in the highest and middle/lowest tertiles of sCD14 levels were comparable. After stratification by sCD14, patients in the lowest tertile of mCD14 were 14.4 times (95% CI 1.90-39.44) more likely to die than patients in the middle/highest tertiles. A significant positive correlation was detected between C-reactive protein and sCD14 levels, providing evidence that sCD14 may serve as an acute phase reactant. In conclusion, low monocyte mCD14 level, unlike the concurrent sCD14 level, predicts 28-d mortality in patients with community acquired infections.

Immune suppression plays a role in the pathogenesis of acute pancreatitis. The purpose was to describe plasma anti-inflammatory cytokines and blood monocyte human leucocyte antigen (HLA)-DR expression, a cellular marker of immune suppression, in relation to clinical outcome in acute pancreatitis.We studied 74 patients with acute pancreatitis admitted within 72 h after symptom onset; 27 had mild disease and 47 severe disease, of whom 20 developed organ failure. Plasma cytokine concentrations and monocyte HLA-DR density were determined at admission and 1, 2, 3, 7, 14 and 21 days later.The levels of interleukin-1 receptor antagonist, interleukin-6 and interleukin-10 correlated inversely to monocyte HLA-DR expression; each marker correlated with disease severity. Interleukin-4, -11 and -13 levels were low. Organ failure occurred at median 36 h (range 8 to 158) after admission and was predicted at admission by the combination of interleukin-6 and interleukin-10 with sensitivity of 95%, specificity of 88% and positive likelihood ratio of 7.6 (95% confidence interval 3.3 to 17). Patients with secondary infections had a lower proportion of HLA-DR positive monocytes than did controls at day 14 (median: 32% versus 65%; n = 7) and at day 21 (median: 49% versus 83%; n = 6), P0.05 each. In the organ failure group, HLA-DR expression did not differ between survivors and non-survivors.Determining the severity of anti-inflammatory reaction at admission and monitoring the course of immune suppression provide a means for predicting clinical outcome in acute pancreatitis.

Objective. To examine CD14 and TNF &#102 gene polymorphisms in early arthritis in relation to clinical outcome. Methods. We studied 141 Caucasians who had had early arthritis 10 to 38 years earlier. We analysed CD14 (-159) and TNF &#102 (- 238, - 308, - 376) polymorphisms using a novel cycle minisequencing method. DNA pools from 370 Caucasian blood donors served as controls. Results. CD14 (-159)C &#77 T allele frequencies were comparable among patients and controls (39% vs 40%). Fifty men and 42 women had recovered while 24 men and six women had chronic spondyloarthropathy (SpA). Mutant T allele frequency was higher in the chronic SpA group than in the recovered group in women (75% vs 32%, relative risk 1.3, 95% confidence limit 1.1 to 1.6, P= 0.011), but not in men (38% vs 44%). All female patients with chronic SpA had CD14 (- 159)T allele and none had a possibly protective TNF &#102 (- 308)G &#77 A allele. Conclusion. Possession of CD14 (- 159)T allele does not increase risk of ReA but may increase susc...

We studied chemiluminescence (CL) responses and chemotaxis of monocytes of patients with early rheumatoid arthritis (RA) before starting anti-rheumatic drug treatment and correlated the data to 2-year prognosis of the patients. Luminol-enhanced CL responses of RA monocytes to N-formylmethionyl-leucyl-phenylalanine or to phorbol myristate acetate, and lucigenin-enhanced responses to opsonized zymosan particles were significantly higher than those of healthy control subjects. Distances of chemotactic, chemokinetic and random migration of RA monocytes were similar to those of control cells. High CL responsiveness correlated with seropositivity but not with presence of HLA-DR4 or that of erosions at 2-year follow-up. The results give credence to the view that monocytes are metabolically activated in early untreated RA, but increased respiratory burst activity does not predict early development of erosions.

Pathogenesis of seronegative spondyloarthropathies such as ankylosing spondylitis and reactive arthritis is not known. Growing evidence indicates that microbial structures such as Chlamydia antigen and Yersinia antigen are present in the inflamed joints of patients with reactive arthritis. Microbial antigens can activate the host's inflammatory mechanisms. After the activation, the course of inflammation can be postulated to be affected by the host factors responsible for amplification of the inflammatory reaction and elimination of the foreign structures. Thus, the amplification, whether strong, moderate, or weak, may contribute to the degree of inflammatory tissue injury in patients with seronegative spondyloarthropathies. This review will discuss the role of increased inflammatory reactivity in the pathogenesis of HLA-B27 associated spondyloarthropathies, with special reference to reactive arthritis triggered by yersinia enteritis.

The pathogenesis of reactive arthritis is multifactorial. The possible pathogenetic mechanisms include the role of microbial antigens which cross-react with the host tissue or trigger cytotoxic immune response. In addition an exaggerated inflammatory response of the host may contribute to the clinical picture of the acute arthritis and its late sequels. In this review, we present data showing that HLA-B27 positive subjects show enhanced neutrophil (PMN) migration and their sera support PMN migration more than HLA-B27 negative sera. Enhanced PMN function is persistent in patients with previous severe reactive arthritis or with late inflammatory sequels. In addition to hyperreactive PMNs, monocytes from patients with previous yersinia arthritis, but also from healthy HLA-B27 positive subjects, respond to stimulation with lipopolysaccharide by enhanced production of inflammatory monokines compared with HLA-B27 negative healthy controls. Thus, hyperreactive phagocytes can contribute to the severe inflammatory complications seen in patients with reactive arthritis. The primed phagocytes can also respond vigorously when stimulated either with endogenous mediators of inflammation or with endotoxin released during a new infection or as a sequel of change in the mucosal permeability described in patients with spondyloarthropathy.

Neutrophils are considered to play an important role in an acute inflammatory reaction; they cause tissue injury both by liberating lysosomal enzymes and generating oxygen-derived free radicals, and they may participate in the regulation of both capillary permeability and the rate of vasodilatation, the two important aspects in microvascular changes at the site of inflammation. Recently, evidence has accumulated that neutrophil function is enhanced in HLA-B27 positive subjects as compared with HLA-B27 negative ones. Such hyperreactive neutrophils may trigger a vicious circle of inflammation and thereby contribute to tissue injury in HLA-B27 associated diseases.

We describe a patient, a 59-year-old woman, who developed erythema nodosum and conjunctivitis after enteritis due to Salmonella typhimurium. The patient was HLA-B27 negative and had circulating immune complexes, as determined by the conglutinin-binding enzyme immunoassay. Immunopathogenesis of the extraintestinal findings is discussed.