Gender differences in management and outcome in non-ST-elevation acute coronary syndrome

Objective

To study gender differences in management and outcome in patients with non‐ST‐elevation acute coronary syndrome.

Design, setting and patients

Cohort study of 53 781 consecutive patients (37% women) from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS‐HIA), with a diagnosis of either unstable angina pectoris or non‐ST‐elevation myocardial infarction. All patients were admitted to intensive coronary care units in Sweden, between 1998 and 2002, and followed for 1 year.

Main outcome measures

Treatment intensity and in‐hospital, 30‐day and 1‐year mortality.

Results

Women were older (73 vs 69 years, p<0.001) and more likely to have a history of hypertension and diabetes, but less likely to have a history of myocardial infarction or revascularisation. After adjustment, there were no major differences in acute pharmacological treatment or prophylactic medication at discharge.Revascularisation was, however, even after adjustment, performed more often in men (OR 1.15; 95% CI, 1.09 to 1.21). After adjustment, there was no significant difference in in‐hospital (OR 1.03; 95% CI, 0.94 to 1.13) or 30‐days (OR 1.07; 95% CI, 0.99 to 1.15) mortality, but at 1 year being male was associated with higher mortality (OR 1.12; 95% CI, 1.06 to 1.19).

Conclusion

Although women are somewhat less intensively treated, especially regarding invasive procedures, after adjustment for differences in background characteristics, they have better long‐term outcomes than men.Since the beginning of the 1990s there have been numerous studies on gender differences in management of acute coronary syndromes (ACS). Many earlier studies,^{1,2,3,4,5,6,7,8} but not all,⁹ found that women were treated less intensively in the acute phase. In some of the studies, after adjustment for age, comorbidity and severity of the disease, most of the differences disappeared.^6,7 There is also conflicting evidence on gender differences in evidence‐based treatment at discharge.^{1,3,5,6,8,10,11}After acute myocardial infarction (AMI), a higher short‐term mortality in women is documented in several studies.^{2,5,6,7,12,13,14} After adjustment for age and comorbidity some difference has usually,^2,5,12,13 but not always,^11,14 remained. On the other hand, most studies assessing long‐term outcome have found no difference between the genders, or a better outcome in women, at least after adjustment.^7,10,13,14 Earlier studies focusing on gender differences in outcome after an acute coronary syndrome have usually studied patients with AMI, including both ST‐elevation myocardial infarction and non‐ST‐elevation myocardial infarction (NSTEMI).^{2,5,6,7,12,13,14} However, the pathophysiology and initial management differs between these two conditions,¹⁵ as does outcome according to gender.^11,16 In patients with NSTEMI or unstable angina pectoris (UAP), women seem to have an equal or better outcome, after adjustment for age and comorbidity.^{1,4,8,11,16,17} Studies on differences between genders, in treatment and outcome, in real life, contemporary, non‐ST‐elevation acute coronary syndrome (NSTE ACS) populations, large enough to make necessary adjustments for confounders, are lacking.The aim of this study was to assess gender differences in background characteristics, management and outcome in a real‐life intensive coronary care unit (ICCU) population, with NSTE ACS.     

Clinical value of multidetector CT coronary angiography as a preoperative screening test before non-coronary cardiac surgery

Objective

Myocardial scintigraphy and/or conventional angiography (CA) are often performed before cardiac surgery in an attempt to identify unsuspected coronary artery disease which might result in significant cardiac morbidity and mortality. Multidetector CT coronary angiography (MDCTCA) has a recognised high negative predictive value and may provide a non‐invasive alternative in this subset of patients. The aim of this study was to evaluate the clinical value of MDCTCA as a preoperative screening test in candidates for non‐coronary cardiac surgery.

Methods

132 patients underwent MDCTCA (Somatom Sensation 16 Cardiac, Siemens) in the assessment of the cardiac risk profile before surgery. Coronary arteries were screened for ⩾50% stenosis. Patients without significant stenosis (Group 1) underwent surgery without any adjunctive screening tests while all patients with coronary lesions ⩾50% at MDCTCA (Group 2) underwent CA.

Results

16 patients (12.1%) were excluded due to poor image quality. 72 patients without significant coronary stenosis at MDCTCA were submitted to surgery. 30 out of 36 patients with significant (⩾50%) coronary stenosis at MDCTCA and CA underwent adjunctive bypass surgery or coronary angioplasty. In 8 patients, MDCTCA overestimated the severity of the coronary lesions (>50% MDCTCA, <50% CA).No severe cardiovascular perioperative events such as myocardial ischaemia, myocardial infarction or cardiac failure occurred in any patient in Group 1.

Conclusions

MDCTCA seems to be effective as a preoperative screening test prior to non‐coronary cardiac surgery. In this era of cost containment and optimal care of patients, MDCTCA is able to provide coronary vessel and ventricular function evaluation and may become the method of choice for the assessment of a cardiovascular risk profile prior to major surgery.Since its introduction in the 1960s,¹ conventional coronary angiography (CA) has been considered the gold standard for the diagnosis of coronary artery disease because of its high contrast, temporal and spatial resolution.^2,3,4 In the past few years, we have witnessed a considerable increase in diagnostic and interventional procedures. Despite the high degree of accuracy (73–89%) of non‐invasive diagnostic tests such as exercise ECG, myocardial scintigraphy and stress‐echocardiography in detecting myocardial ischaemia,⁵ about 20% of patients undergoing CA due to a positive result of these non‐invasive tests, had no evidence of coronary lesions.^6,7Multidetector CT (MDCT), introduced into clinical practice in 2000, has demonstrated excellent technical characteristics for coronary artery evaluation. Results in the literature show a high degree of diagnostic accuracy in detecting significant coronary lesions and, particularly, an excellent capability of excluding them, due to negative predictive values ranging from 96 to 99%.^{8,9,10,11,12,13,14,15,16,17,18}Patients who are candidates for major non‐coronary cardiac or vascular surgery, such as heart valve replacement, aortic aneurysm and aortic dissection, require a complete assessment of potentially dangerous co‐morbidities. There is a 5 to 10% perioperative cardiac morbidity rate during vascular surgery, even in patients at low risk for coronary disease.¹⁹ According to Paul et al.²⁰ there is a 17% risk of severe multivessel disease in low clinical risk asymptomatic patients undergoing vascular surgery. American College of Cardiology/American Heart Association (ACC/AHA) guidelines for preoperative evaluation before major surgery recommend stratification of ischaemic heart disease with clinical and non‐invasive tests.^19,20,21,22 The diagnostic accuracy is 68 to 77% for exercise ECG and 73 to 85% for stress‐echocardiography. Myocardial scintigraphy provides an accuracy of 87–89% in patients with normal resting ECG, with a radiation exposure ranging from 4.6 to 20 mSv,²³ almost equivalent to MDCT coronary angiography (MDCTCA). However, for certain high‐risk patients, ACC guidelines suggest proceeding directly with coronary angiography rather than performing a non‐invasive test. Therefore, in clinical practice, CA is often performed before major vascular or cardiac surgery. Considering that millions of surgical procedures are probably performed every year worldwide (eg, 95 000 heart valve replacements/year in the USA),^6,7 several hundred thousand negative CAs are still performed.After some years of validation studies comparing MDCTCA with CA, studies on clinical utility are now warranted to demonstrate whether and how this technique can change and improve the current management of patients. The purpose of this study is to evaluate the clinical impact of MDCTCA as a preoperative screening test for cardiac risk assessment in patients who are candidates for major non‐coronary cardiac surgery and who are asymptomatic for ischaemic heart disease.     

A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age

Background

Poor prognosis in heart failure (HF) patients with diabetes is often attributed to increased co‐morbidity and advanced disease. Further, this effect may be worse in women.

Objective

To determine whether the effect of diabetes on outcomes and the sex‐related variation persisted in a propensity score‐matched HF population, and whether the sex‐related variation was a function of age.

Methods

Of the 7788 HF patients in the Digitalis Investigation Group trial, 2218 had a history of diabetes. Propensity score for diabetes was calculated for each patient using a non‐parsimonious logistic regression model incorporating all measured baseline covariates, and was used to match 2056 (93%) diabetic patients with 2056 non‐diabetic patients.

Results

All‐cause mortality occurred in 135 (25%) and 216 (39%) women without and with diabetes (adjusted HR = 1.67; 95% CI = 1.34 to 2.08; p<0.001). Among men, 535 (36%) and 609 (41%) patients without and with diabetes died from all causes (adjusted HR = 1.21; 95% CI = 1.07 to 1.36; p = 0.002). Sex–diabetes interaction (overall adjusted p<0.001) was only significant in patients ⩾65 years (15% absolute risk increase in women; multivariable p for interaction = 0.005), but not in younger patients (2% increase in women; p for interaction = 0.173). Risk‐adjusted HR (95% CI) for all‐cause hospitalisation for women and men were 1.49 (1.28 to 1.72) and 1.21 (1.11 to 1.32), respectively, also with significant sex–diabetes interaction (p = 0.011).

Conclusions

Diabetes‐associated increases in morbidity and mortality in chronic HF were more pronounced in women, and theses sex‐related differences in outcomes were primarily observed in elderly patients.Diabetes is common in heart failure (HF) and is associated with poor outcomes.^1,2 HF patients with diabetes are sicker and have a higher burden of co‐morbidity than those without diabetes.^1,2 Diabetes is also associated with activation of the renin–angiotensin–aldosterone and sympathetic nervous systems.^3,4 There is mounting evidence that diabetes adversely affects collagen production in fibroblasts and calcium homeostasis in cardiac myocytes.^5,6 However, it is not clear to what extent the diabetes‐associated poor outcomes in HF are due to the direct effects of diabetes.Although outcome‐based multivariable risk adjustment models can account for these confounding covariates to some extent, concerns for residual bias limit interpretation of these results.⁷ To address this concern, propensity score matching can be used to assemble cohorts of patients with and without an exposure who would be well balanced in all measured baseline covariates.^8,9,10 More importantly, as investigators remain blinded during the design phase of a randomised clinical trial, this process of bias reduction and study cohort assembly can be done without any knowledge or use of the outcomes data, and the magnitude of bias reduction may be objectively assessed using standardised differences.^7,9,10,11Data from patients with coronary artery disease and elderly patients hospitalised with systolic HF suggest that the effect of diabetes might be worse in women than in men.^12,13,14 However, little is known about the sex‐related variation in the effect of diabetes on outcomes in a more stable younger ambulatory patient population with mild to moderate systolic and diastolic HF. It is also unknown if this sex‐related difference in the effect of diabetes on HF is a function of age. The purpose of this study thus is to determine the effect of diabetes on mortality and hospitalisation in propensity score‐matched ambulatory HF patients and to determine if the effect varies by sex and if the sex‐related differences vary by age.     

Joint-specific hand symptoms and self-reported and performance-based functional status in African Americans and Caucasians: The Johnston County Osteoarthritis Project

Objective

To assess associations between joint‐specific hand symptoms and self‐reported and performance‐based functional status.

Methods

Participants were from the population‐based Johnston County Osteoarthritis Project. Symptoms in the distal interphalangeal (DIP), proximal interphalangeal (PIP), first carpometacarpal (CMC), and metacarpophalangeal (MCP) joints were assessed on a 30‐joint diagram of both hands. Self‐reported function was assessed by Health Assessment Questionnaire (HAQ) and performance‐based function by timed repeated chair stands and 8‐foot walk time. Separate multiple logistic regression models examined associations between symptoms in specific hand joint groups, symptoms in ⩾2 hand joint groups and number of symptomatic hand joints, and functional status measures, controlling for age, race/ethnicity, sex, body mass index, radiographic knee and hip OA, knee and hip symptoms and depressive symptoms.

Results

Those with symptomatic hand joint groups were more likely than those without these complaints to report more difficulty and require longer times for performance measures. Those with 2 or more symptomatic hand joint groups were more likely to have higher HAQ scores (OR = 1.97 (1.53 to 2.53)) and require more time to complete 5 chair stands (OR = 1.98 (1.23 to 3.18)) and the 8 foot walk test (OR = 1.49 (1.12 to 1.99)).

Conclusions

Joint‐specific hand symptoms are associated with difficulty performing upper‐ or lower‐extremity tasks, independent of knee and hip OA and symptoms, suggesting that studies examining functional status in OA should not ignore symptomatic joints beyond the joint site of interest, even when functional measures appear to be specific for the joint site under study.Osteoarthritis (OA) is a common cause of pain and disability.^1,2 Pain, aching or stiffness attributed to hand OA is associated with functional limitations in activities requiring use of the hands.^3,4 Individuals with OA of both the hands and knees have higher (worse) Health Assessment Questionnaire (HAQ) scores than those with isolated hand or knee OA.⁵ Unrecognised concomitant hand symptoms could potentially confound studies using the HAQ to follow symptoms of hip or knee OA, especially since a significant number of patients with isolated hip or knee OA alone will develop hand OA over time.⁵ Despite this, investigations of the impact of upper‐ or lower‐extremity OA traditionally use questions, functional tests or even selected components of the HAQ restricted to upper‐ or lower‐extremity function.^4,6,7 We have previously reported an association between knee pain and difficulty performing not just lower‐extremity tasks but upper‐extremity tasks as well, suggesting possible concomitant upper‐extremity involvement in the participants in the Johnston County Osteoarthritis Project.⁸ In this study, we examined associations between joint‐specific hand symptoms, as surrogate measures of hand OA, and self‐reported and performance‐based measures of functional status. Additionally, we evaluated whether these associations were independent of radiographic hip and knee OA and hip and knee symptoms, and whether these associations varied by race/ethnicity, sex, and the presence of knee or hip symptoms.     

Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis

Background/Aims

Recent evidence has implicated the involvement of aquaporins (AQPs) in cellular functions that are unrelated to transepithelial water transport. Although AQPs are expressed in the gastrointestinal tract, their importance has so far been unclear. AQP3 is a water/glycerol transporter expressed at the basolateral membrane of colonic epithelial cells. The aim of this study was to investigate the involvement of AQP3 in enterocyte proliferation using mouse models of inflammatory bowel disease.

Methods

Expression and function of AQP3 in mouse colonic epithelium were established. Colitis was induced in wild‐type and AQP3 null mice by oral dextran sulphate administration or intracolonic acetic acid administration. Outcome measures included clinical disease severity, survival, pathology and cellular responses. Some mice were administered glycerol to test whether disease progression could be altered.

Results

AQP3 null mice given dextran sulphate developed severe colitis after 3 days, with colonic haemorrhage, marked epithelial cell loss and death. Wild‐type mice, which had comparable initial colonic damage as assessed by cell apoptosis, developed remarkably less severe colitis, surviving to >8 days. Cell proliferation was greatly reduced in AQP3 null mice. Oral glycerol administration significantly improved survival and reduced the severity of colitis in AQP3 null mice. Survival was also reduced in AQP3 null mice in the acetic acid model.

Conclusions

The results implicate a novel role for AQP3 in enterocyte proliferation that is probably related to its glycerol‐transporting function. AQP3 is thus a potential target for therapy of intestinal diseases associated with enterocyte destruction.The aquaporins (AQPs) are a family of water channels expressed in many epithelial, endothelial and other cell types. They facilitate transepithelial water transport in kidney tubules for urine concentration, and in glandular, choroidal and ciliary epithelia for fluid secretion.^1,2 AQPs in non‐epithelial tissues in the central nervous system and eye are also involved in the regulation of tissue hydration. Recently, analysis of transgenic mice lacking specific AQPs has revealed new cellular roles for AQPs that are unrelated to transcellular water transport.³ We found impaired angiogenesis in AQP1‐deficient mice as a consequence of reduced endothelial cell migration,⁴ which may be caused by slowed water movement into lamellipodia at the leading edge of migrating cells. A subset of AQPs (AQPs 3, 7 and 9), called ‘aquaglyceroporins'', transport water as well as glycerol, and possibly other small solutes. Mice lacking AQP3 have dry skin and delayed epidermal healing, with reduced glycerol content in epidermis and stratum corneum,^5,6 caused by impaired glycerol transport from the dermis through the normally AQP3‐expressing basal keratinocytes. Recent studies provided evidence for a new role for AQP3 in cell proliferation. Mice lacking AQP3 were found to have significantly impaired epidermal proliferation in a wound healing model,⁷ and impaired corneal epithelial cell proliferation after epithelial injury.⁸ Mice lacking AQP7 manifest age‐dependent adipocyte hypertrophy and glycerol accumulation,⁹ which we proposed is caused by reduced glycerol exit from the normally AQP7‐expressing adipocytes.AQPs are expressed strongly in gastrointestinal organs including the stomach (parietal cells), liver (hepatocytes and cholangiocytes), pancreas (acinar epithelia), gallbladder (epithelium), small intestine (lacteals, enterocytes) and colon (colonocytes).^10,11 Consequently, roles for AQPs in the secretion of bile and pancreatic fluid have been postulated, as well as in intestinal fluid absorption and secretion. However, phenotype analysis of AQP1, AQP4 and AQP8 knockout mice has revealed little or no consequence of AQP deletion on major gastrointestinal fluid‐transporting functions.^{12,13,14,15,16} The absence of overt gastrointestinal phenotypes in AQP‐deficient mice is surprising in view of the renal, central nervous system, ocular, glandular, cutaneous and other phenotypes found in these mice, particularly since the magnitude of gastrointestinal fluid transport is second only to that in kidney.The epithelium lining the intestine maintains its architecture by a balance between the continuous processes of epithelial cell generation from clonal stem cells¹⁷ at the base of intestinal crypts, and death of cells near the luminal surface. Recent evidence has suggested dysregulation of these processes in inflammatory bowel diseases (IBDs) such as ulcerative colitis, and has emphasised the importance of cell proliferation in disease progression.^18,19 There is evidence for a crucial role for Toll‐like receptor (TLR) signalling and commensal bacteria in the initiation and transduction of the inflammatory and tissue repair responses.^20,21 TLR‐4 null mice and related MyD88 null mice show significantly more severe disease progression in murine models of colitis as a result of impaired epithelial cell proliferation.²⁰Here, we present evidence for a new AQP function in the gastrointestinal tract. We found remarkably greater colonic pathology and mortality in mice lacking AQP3 than in wild‐type mice in experimental models of colitis, with impaired epithelial cell proliferation at the base of colonic crypts in the null mice. The motivations for this study included the strong expression of AQP3 in colonic epithelial cells that undergo rapid turnover,¹⁷ and, as mentioned above, the impairment of epidermal and corneal cell proliferation in AQP3 deficiency.^7,8 We used the dextran sulphate and intracolonic acetic acid models of colitis^21,22,23,24 to induce epithelial damage and restitution in the colon. The primary model used was the dextran sulphate model, a well‐described oral model of colitis. In order to verify the findings using a direct damage, non‐oral model, we also used intracolonic instillation of acetic acid.^25,26 Enterocyte turnover is strongly stimulated in these models, which we predicted could expose defects in enterocyte proliferation and/or migration in AQP3 deficiency. Consequences of the findings here include the potential involvement of AQP3 in epithelial cell proliferation in a variety of intestinal inflammatory diseases, and the possibility of new therapies based on pharmacological modulation of AQP3 expression.     

A closer look at non-Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case-control study

Objective

To investigate risk factors for non‐Hodgkin''s lymphoma (NHL) and analyse NHL subtypes and characteristics in patients with systemic lupus erythematosus (SLE).

Methods

A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case control study on SLE patients who developed NHL during this observation period was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed. Tissue specimens on which the lymphoma diagnosis was based were retrieved and reclassified according to the WHO classification. NHLs of the subtype diffuse large B cell lymphoma (DLBCL) were subject to additional immunohistochemical staining using antibodies against bcl‐6, CD10 and IRF‐4 for further subclassification into germinal centre (GC) or non‐GC subtypes.

Results

16 patients with SLE had NHL, and the DLBCL subtype dominated (10 cases). The 5‐year overall survival and mean age at NHL diagnosis were comparable with NHL in the general population—50% and 61 years, respectively. Cyclophosphamide or azathioprine use did not elevate lymphoma risk, but the risk was elevated if haematological or sicca symptoms, or pulmonary involvement was present in the SLE disease. Two patients had DLBCL‐GC subtype and an excellent prognosis.

Conclusions

NHL in this national SLE cohort was predominated by the aggressive DLBCL subtype. The prognosis of NHL was comparable with that of the general lymphoma population. There were no indications of treatment‐induced lymphomas. Molecular subtyping could be a helpful tool to predict prognosis also in SLE patients with DLBCL.Evidence of an increased risk to develop haematological malignancy, and especially non‐Hodgkin''s lymphoma (NHL) in autoimmune diseases, has been gathered since the 1970s. First studies of Sjögren''s syndrome,¹ then rheumatoid arthritis (RA)² and now in the last decade studies from uni‐/multicentre SLE cohorts^3,4,5,6,7,8 and national SLE cohorts^9,10 have consistently shown a markedly increased risk of NHLs. As for NHL subtype, knowledge is more limited. RA and SLE share several disease manifestations like arthritis and “extra‐articular manifestations” such as serositis, sicca symptoms and interstitial inflammatory lung disease. In RA, a pronounced over‐representation of diffuse large B cell lymphoma (DLBCL) has been reported from a large population‐based cohort.¹¹ This lymphoma subtype was also the most frequent in an international multicentre study with lupus patients.¹² In Sjögren''s syndrome, approximately 85% are MALT lymphomas,¹³ although a recent study from a mono‐centre primary Sjögren''s syndrome cohort—with patients fulfilling the American–European Consensus Group criteria¹⁴—showed a predominance of DLBCL.¹⁵The pathophysiological mechanisms for the enhanced risk of developing NHL in patients with chronic inflammatory diseases are still not fully understood. Similarities of a variety of immunological disturbances that characterise both rheumatic conditions and lymphomas have been suggested as a linkage between these disorders as well as a possible potentiation of immunosuppressive drugs or certain viral infections, especially Epstein–Barr virus (EBV).^5,16Recently, advances in molecular characterisation have enabled more detailed subclassification of lymphomas based on the molecular expression of the tumour cells. For DLBCL, two prognostic groups have been identified among DLBCL in the general lymphoma population depending on the resemblance of gene expression profile with normal germinal centre (GC) or activated B cells by using global gene expression profiling^17,18 and immunophenotyping of tumour cells.^19,20 The GC DLBC lymphomas had a significantly better survival than those with non‐GC subtype.^17,18,19,20 No such subtyping has been reported in SLE patients.In a previous register study of a population‐based national Swedish SLE cohort, a threefold increased risk of lymphoma was found.¹⁰ This nested case‐control study focuses on those SLE patients that developed NHL. Information on clinical manifestations and pharmacological (cytotoxic) treatment of the SLE disease was retrieved from patient records. The lymphomas were re‐examined and reclassified, and DLBCLs were further divided into GC or non‐GC subtypes by immunohistochemistry. The presence of EBV in the lymphomas was also analysed.     

Endothelial protein C receptor is overexpressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes

Objectives

(1) To investigate whether inflammatory synovial tissues from patients with rheumatoid arthritis (RA) express endothelial protein C receptor (EPCR) and (2) to determine the major cell type(s) that EPCR is associated with and whether EPCR functions to mediate the effects of activated protein C (APC) on these cells.

Methods

EPCR, CD68 and PC/APC in synovial tissues were detected by immunostaining and in situ PCR. Monocytes were isolated from peripheral blood of patients with RA and treated with APC, lipopolysaccharide (LPS), and/or EPCR blocking antibody RCR252. Cells and supernatants were collected for RT‐PCR, western blotting, enzyme‐linked immuosorbent assay and chemotaxis assay.Results: EPCR was expressed by both OA and RA synovial tissues but was markedly increased in RA synovium. EPCR was colocalised with PC/APC mostly on CD68 positive cells in synovium. In RA monocytes, APC upregulated EPCR expression and reduced monocyte chemoattractant protein‐1‐induced chemotaxis of monocytes by approximately 50%. APC also completely suppressed LPS‐stimulated NF‐κB activation and attenuated TNF‐α protein by more than 40% in RA monocytes. The inhibitory effects of APC were reversed by RCR252, indicating that EPCR is required.

Conclusions

Our results demonstrate for the first time that EPCR is expressed by synovial tissues, particularly in RA, where it co‐localises with PC/APC on monocytes/macrophages. In addition, APC inhibits the migration and activation of RA monocytes via EPCR. These inhibitory effects on RA monocytes suggest that PC pathway may have a beneficial therapeutic effect in RA.Rheumatoid arthritis (RA) is a chronic autoimmune disease with persistent inflammation of multiple synovial joints, which results in progressive tissue destruction of bone and cartilage.^1,2 It is characterised by the infiltration of inflammatory cells (neutrophils, monocytes and lymphocytes) into the synovial compartment and the production of inflammatory mediators. In RA, monocytes migrate into the synovium to become activated macrophages where they secrete significant amounts of inflammatory cytokines such as interleukin (IL)‐1, tumour necrosis factor (TNF)‐α and proteases, which are important in initiating, propagating and maintaining synovial inflammation.³ Macrophages can also differentiate into dendritic cells and osteoclasts,⁴ the latter being recognised as the key cellular effectors of pathological bone erosion in arthritis.⁵ In rheumatoid synovial sections, most synovial lining cells are highly activated macrophage‐like cells functioning as antigen‐processing and antigen‐presenting cells to T lymphocytes.⁶ Macrophages are critically involved in the pathogenesis of RA, not only by producing a variety of pro‐inflammatory cytokines and chemokines, but also by contributing to the cartilage and bone destruction.Activated protein C (APC) is a 61‐kDa serine protease derived from its vitamin K‐dependent plasma precursor, protein C (PC). Activation of PC occurs on the endothelial cell surface and is triggered by a complex formed between thrombin and thrombomodulin. The conversion to APC is augmented in the presence of its specific receptor, endothelial protein C receptor (EPCR),⁷ which is expressed on the surface of endothelial cells, keratinocytes⁸ and some leucocytes, including eosinophils, neutrophils and monocytes.⁹APC acts as an anticoagulant by neutralising the procoagulant activities of factors Va and VIIIa and inhibiting thrombin generation. In addition, APC exerts significant anti‐inflammatory properties, associated with a decrease in pro‐inflammatory mediators and a reduction of leucocyte recruitment.¹⁰ Many anti‐inflammatory properties of APC are mediated through EPCR, which itself can independently exert anti‐inflammatory effects.^11,12,13 For example, severe EPCR deficiency adversely affects survival and cardiac function of mice subjected to challenge by endotoxin infusion.¹³ Baboons treated with an antibody to block PC binding to EPCR respond lethally to normally sublethal concentrations of E coli and exhibit disseminated intravascular coagulation, intense neutrophil influx into the tissues and elevation of inflammatory cytokines, indicating that EPCR provides a critical step in the host defense against E coli.¹² Over expression of EPCR protects transgenic mice from endotoxin‐induced injury.¹⁴ In addition, recent findings suggest that EPCR is required for embryo survival and development.^15,16,17PC/APC is elevated in RA synovial fluid and synovial joints, where it co‐localises with MMP‐2.¹⁸ However, whether EPCR is present in the inflammatory joint is unknown. The purpose of this study was: (1) to determine whether inflammatory (RA) synovial tissue expresses EPCR and if so whether these levels are higher than non‐inflammatory OA synovial tissue; and (2) to elucidate the major cell type(s) EPCR is associated with and whether it functions to mediate the effects of APC on these cells.     

Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis

Objective

To examine the relationship between longitudinal fluctuations in synovitis with change in pain and cartilage in knee osteoarthritis.

Methods

Study subjects were patients 45 years of age and older with symptomatic knee osteoarthritis from the Boston Osteoarthritis of the Knee Study. Baseline and follow‐up assessments at 15 and 30 months included knee magnetic resonance imaging (MRI), BMI and pain assessment (VAS) over the last week. Synovitis was scored at 3 locations (infrapatellar fat pad, suprapatellar and intercondylar regions) using a semiquantitative scale (0–3) at all 3 time points on MRI. Scores at each site were added to give a summary synovitis score (0–9).

Results

We assessed 270 subjects whose mean (SD) age was 66.7 (9.2) years, BMI 31.5 (5.7) kg/m²; 42% were female. There was no correlation of baseline synovitis with baseline pain score (r = 0.09, p = 0.17). The change in summary synovitis score was correlated with the change in pain (r = 0.21, p = 0.0003). An increase of one unit in summary synovitis score resulted in a 3.15‐mm increase in VAS pain score (0–100 scale). Effusion change was not associated with pain change. Of the 3 locations for synovitis, changes in the infrapatellar fat pad were most strongly related to pain change. Despite cartilage loss occurring in over 50% of knees, synovitis was not associated with cartilage loss in either tibiofemoral or patellofemoral compartment.

Conclusions

Change in synovitis was correlated with change in knee pain, but not loss of cartilage. Treatment of pain in knee osteoarthritis (OA) needs to consider treatment of synovitis.The cause of pain in knee osteoarthritis remains elusive as the primary site of pathology in OA, cartilage, has no pain fibres.¹ Many other structures around the knee such as the periosteum, subchondral bone, the fat pad, capsule and, inconsistently, the synovium have been shown to contain nociceptive fibres.¹ In addition, inflammation itself appears to play a role in increasing input from peripheral nociceptors.² Biopsies of patients with both early and late knee OA have shown low‐grade chronic synovitis with production of pro‐inflammatory cytokines.^3,4Magnetic resonance imaging (MRI) allows evaluation of multiple structures within the knee, including synovium, cartilage, menisci, bone marrow lesions and effusion. In cross‐sectional studies of MRI in knee osteoarthritis (OA), bone‐marrow lesions, periarticular lesions, knee effusions and synovitis have been shown to be more often present in persons with knee pain than in persons with a comparable amount of radiographic knee osteoarthritis but without pain.^5,6,7,8 Fernandez‐Madrid et al demonstrated that synovial thickening seen on non‐contrast enhanced MRI in the infrapatellar region of knees with OA showed low‐grade synovial inflammation on biopsy. This feature was present in 73% of knees with early OA.⁹We have previously shown that this synovial thickening is present in persons with knee pain and OA much more often than in persons with OA but without pain.⁷ Among those with pain, the presence of MRI synovial thickening identified those with more severe pain. While this evidence suggests that synovial thickening may affect pain, these data are cross‐sectional, making it impossible to evaluate the temporal relation of pain with synovial thickening. More persuasive evidence would emanate from a longitudinal study in which fluctuations in synovial thickening could be tied to fluctuations in the severity of knee pain. Herein, we provide such evidence. Our aims were to study the association between baseline and longitudinal changes in MRI‐detected synovitis and changes in knee pain, and also to study the association between baseline and longitudinal changes in synovitis and cartilage loss in patients with symptomatic knee OA.     

Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission

Objective

The aim of the study was to compare time‐trends in mortality rates and treatment patterns between patients with and without diabetes based on the Swedish register of coronary care (Register of Information and Knowledge about Swedish Heart Intensive Care Admission [RIKS‐HIA]).

Methods

Post myocardial infarction mortality rate is high in diabetic patients, who seem to receive less evidence‐based treatment. Mortality rates and treatment in 1995–1998 and 1999–2002 were studied in 70 882 patients (age <80 years), 14 873 of whom had diabetes (the first registry recorded acute myocardial infarction), following adjustments for differences in clinical and other parameters.

Results

One‐year mortality rates decreased from 1995 to 2002 from 16.6% to 12.1% in patients without diabetes and from 29.7% to 19.7%, respectively, in those with diabetes. Patients with diabetes had an adjusted relative 1‐year mortality risk of 1.44 (95% CI 1.36 to 1.52) in 1995–1998 and 1.31 (95% CI 1.24 to 1.38) in 1999–2002. Despite improved pre‐admission and in‐hospital treatment, diabetic patients were less often offered acute reperfusion therapy (adjusted OR 0.85, 95% CI 0.80 to 0.90), acute revascularisation (adjusted OR 0.78, 95% CI 0.69 to 0.87) or revascularisation within 14 days (OR 0.80, 95% CI 0.75 to 0.85), aspirin (OR 0.90, 95% CI 0.84 to 0.98) and lipid‐lowering treatment at discharge (OR 0.81, 95% CI 0.77 to 0.86).

Conclusion

Despite a clear improvement in the treatment and myocardial infarction survival rate in patients with diabetes, mortality rate remains higher than in patients without diabetes. Part of the excess mortality may be explained by co‐morbidities and diabetes itself, but a lack of application of evidence‐based treatment also contributes, underlining the importance of the improved management of diabetic patients.Patients with diabetes have higher short‐ and long‐term mortality rates after acute myocardial infarction (MI) than those without diabetes.^1,2,3,4 This pattern has remained even after the introduction of modern therapeutic principles.^5,6,7 According to US mortality rate trends diabetic patients have not experienced a similar mortality rate reduction as that seen in non‐diabetic patients.^8,9,10 Less use of evidence‐based treatment has been suggested as an important explanation.^{4,10,11,12,13,14} The systematic use of such therapy should decrease hospital mortality rate in diabetic patients so that it approaches that in those without diabetes.¹⁵The Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS‐HIA), covering almost all Swedish patients with MI, offers detailed information on treatment patterns and prognosis in unselected patients with and without diabetes. The aim of this study is to analyse time trends in treatment patterns and prognosis in order to see whether management has improved.     

Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome

Objective

S100A12 is a pro‐inflammatory protein that is secreted by granulocytes. S100A12 serum levels increase during inflammatory bowel disease (IBD). We performed the first study analysing faecal S100A12 in adults with signs of intestinal inflammation.

Methods

Faecal S100A12 was determined by ELISA in faecal specimens of 171 consecutive patients and 24 healthy controls. Patients either suffered from infectious gastroenteritis confirmed by stool analysis (65 bacterial, 23 viral) or underwent endoscopic and histological investigation (32 with Crohn''s disease, 27 with ulcerative colitis, and 24 with irritable bowel syndrome; IBS). Intestinal S100A12 expression was analysed in biopsies obtained from all patients. Faecal calprotectin was used as an additional non‐invasive surrogate marker.

Results

Faecal S100A12 was significantly higher in patients with active IBD (2.45 ± 1.15 mg/kg) compared with healthy controls (0.006 ± 0.03 mg/kg; p<0.001) or patients with IBS (0.05 ± 0.11 mg/kg; p<0.001). Faecal S100A12 distinguished active IBD from healthy controls with a sensitivity of 86% and a specificity of 100%. We also found excellent sensitivity of 86% and specificity of 96% for distinguishing IBD from IBS. Faecal S100A12 was also elevated in bacterial enteritis but not in viral gastroenteritis. Faecal S100A12 correlated better with intestinal inflammation than faecal calprotectin or other biomarkers.

Conclusions

Faecal S100A12 is a novel non‐invasive marker distinguishing IBD from IBS or healthy individuals with a high sensitivity and specificity. Furthermore, S100A12 reflects inflammatory activity of chronic IBD. As a marker for neutrophil activation, faecal S100A12 may significantly improve our arsenal of non‐invasive biomarkers of intestinal inflammation.The etiology of inflammatory bowel disease (IBD) consisting of ulcerative colitis and Crohn''s disease involves complex interactions among susceptibility genes, the environment, and the immune system. These interactions lead to a cascade of events that involve the activation of neutrophils, production of proinflammatory mediators, and tissue damage.¹ As intestinal symptoms are a frequent cause of referrals to gastroenterologists, it is crucial to differentiate between non‐inflammatory irritable bowel syndrome (IBS) and IBD. To date, there is a lack of biological markers to determine intestinal inflammation.^2,3 Therefore, invasive procedures are required to confirm the diagnosis of IBD. Furthermore, the natural history of chronic IBD is characterised by an unpredictable variation in the degree of inflammation. Biological markers are needed to confirm remission, detect early relapses or local reactivation, and to monitor anti‐inflammatory therapies reliably. Whereas serum markers of inflammation are still not very helpful,^3,4,5 assays that determine intestinal inflammation by detecting neutrophil‐derived products in stool show great potential.⁶An important mechanism in the initiation and perturbation of inflammation in IBD is the activation of innate immune mechanisms.^7,8 Among the factors released by infiltrating neutrophils are proteins of the S100 family.^9,10 One example is calprotectin, which is detectable in the serum and stool during intestinal inflammation.¹¹ Calprotectin was initially described as a protein of 36 kDa, but was later characterised as a complex of two distinct S100 proteins, S100A8 and S100A9.^12,13,14 In recent years, calprotectin has been proposed as a faecal marker of gut inflammation reflecting the degree of phagocyte activation.^{6,15,16,17,18,19,20} Unfortunately, variation in faecal calprotectin assays still impedes the routine use of this marker as a sole parameter in clinical practice. The observed variation may be caused by the broad expression pattern of calprotectin, which is found in granulocytes as well as monocytes and is also inducible in epithelial cells.^21,22 In this context, the elevation in lactose intolerance is notable.^16,17,23S100A12 is more restricted to granulocytes. It is secreted by activated neutrophils and is abundant in the intestinal mucosa of patients with IBD.^9,24 Overexpression at the site of inflammation and correlation with disease activity in a variety of inflammatory disorders underscore the role of this granulocytic protein as a proinflammatory molecule.²⁵ The binding of S100A12 to the receptor for advanced glycation endproducts (RAGE) leads to the long‐term activation of nuclear factor kappa B, which promotes inflammation.²⁶ In mouse models of colitis, blocking the interaction of S100A12 with RAGE has been proved to attenuate inflammation. Data on murine models of colitis as well as human IBD point to an important role for S100A12 during the pathogenesis of these disorders.^9,26,27In a previous study, we demonstrated that S100A12 is overexpressed during chronic active IBD and serves as a useful serum marker for disease activity in patients with IBD.⁹ De Jong et al.²⁸ recently reported that S100A12 can be detected in the stool of children with Crohn''s disease. The aim of our present study was thus to analyse S100A12 in stool samples as well as its expression in the intestinal tissue of patients with confirmed IBD or IBS and in the stool of a normal control group. We correlated faecal S100A12 levels with endoscopic and histological findings in the same patients and investigated the diagnostic accuracy of S100A12 to detect intestinal inflammation.     

Disease management programme for secondary prevention of coronary heart disease and heart failure in primary care: a cluster randomised controlled trial

Aims

To evaluate the effect of a disease management programme for patients with coronary heart disease (CHD) and chronic heart failure (CHF) in primary care.

Methods

A cluster randomised controlled trial of 1316 patients with CHD and CHF from 20 primary care practices in the UK was carried out. Care in the intervention practices was delivered by specialist nurses trained in the management of patients with CHD and CHF. Usual care was delivered by the primary healthcare team in the control practices.

Results

At follow up, significantly more patients with a history of myocardial infarction in the intervention group were prescribed a beta‐blocker compared to the control group (adjusted OR 1.43, 95% CI 1.19 to 1.99). Significantly more patients with CHD in the intervention group had adequate management of their blood pressure (<140/85 mm Hg) (OR 1.61, 95% CI 1.22 to 2.13) and their cholesterol (<5 mmol/l) (OR 1.58, 95% CI 1.05 to 2.37) compared to those in the control group. Significantly more patients with an unconfirmed diagnosis of CHF had a diagnosis of left ventricular systolic dysfunction confirmed (OR 4.69, 95% CI 1.88 to 11.66) or excluded (OR 3.80, 95% CI 1.50 to 9.64) in the intervention group compared to the control group. There were significant improvements in some quality‐of‐life measures in patients with CHD in the intervention group.

Conclusions

Disease management programmes can lead to improvements in the care of patients with CHD and presumed CHF in primary care.Cardiovascular diseases including coronary heart disease (CHD) and chronic heart failure (CHF) are the main cause of morbidity and mortality in most European countries.¹ Mortality from cardiovascular disease has declined over the last 30 years, a trend which has been attributed to secondary prevention therapies.^2,3 However, European surveys have shown considerable potential for improved levels of secondary prevention in people with established CHD.⁴ Studies in primary care, where most of these patients are managed, have also reported considerable potential to further increase secondary prevention through medical and lifestyle interventions.^5,6 “Medical” measures include aspirin therapy and blood pressure and lipid control, while “lifestyle” measures include increased exercise, dietary modification and smoking cessation.⁵ CHF is also a highly prevalent, chronic condition with high mortality and morbidity. It is increasing in prevalence and the public health burden from CHF is therefore likely to rise substantially over the next 10 years.⁷ The quality of life of patients with CHF is worse than for most chronic conditions managed in primary care and five‐year survival is worse than for many malignant conditions.⁸ However, appropriate treatment, including inhibitors of the renin‐angiotensin‐aldosterone system and beta‐blockers, has the potential to reduce hospitalisation and mortality in these patients.^9,10 The task of implementing a comprehensive package of effective measures for large numbers of patients has been described as daunting.⁵ It is therefore important to develop implementation strategies that are practical and effective. Many patients with CHF are incorrectly diagnosed and inadequately treated in primary care¹¹ and obstacles to appropriate primary care management include lack of knowledge, fear of complications with pharmacological treatments, lack of time and limited facilities for investigations.^12,13Systematic reviews indicate that secondary prevention programmes improve the process of care, reduce admissions to hospital and enhance quality of life or functional status in patients with CHD.¹⁴ Similarly, systematic reviews of disease management programmes in CHF suggest that specialised, multidisciplinary follow‐up can reduce hospitalisation and may lead to cost saving.^15,16,17 However, all the CHF trials included in these systematic reviews were conducted in highly specialised centres and recruited patients following discharge after hospitalisation. The applicability of the available CHF management programmes to countries with a primary care‐based healthcare system has therefore recently been questioned.¹⁸To achieve improved secondary prevention of CHD and CHF, primary care will need to adopt a systematic approach. Although disease management clinics for the management of CHD in primary care can improve patients'' outcomes,⁵ there are no such studies in the management of patients with CHF. Since the majority of patients with CHF will also have CHD,¹⁹ we investigated the effect of a disease management programme for patients with either or both conditions in primary care.     

Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy

Objective

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus‐eluting stent (SES) implantation.

Methods

Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, at 6 months and at 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.

Results

The maximum NSC increased from 6 months to 2 years (mean (SD) 1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus‐related adverse events, new thrombus formation was found in 5% of 6‐month, and in 20% of 2‐year follow‐up evaluations. The prevalence of thrombus inside the SES at baseline, 6 months and 2 years was similar (40%, 40% and 30%, respectively; p = NS).

Conclusions

Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not uncommon.Recently, occurrence of late stent thrombosis (LST) after drug‐eluting stent implantation has became a major clinical concern.^1,2,3 A long‐term follow‐up study demonstrated that LST occurs at a constant rate of 0.6% a year for up to 3 years after drug‐eluting stent implantation.³ Pathological investigation showed that delayed arterial healing, characterised by an incomplete endothelialisation and persistence of fibrin, has a key role in the occurrence of LST.^4,5 Moreover, a powerful predictor of LST is the existence of uncovered struts without endothelialisation.⁵ We therefore suggested that the uncovered struts of a sirolimus‐eluting stent (SES) remain for an extended period of time.Coronary angioscopy provides direct visualisation of the lumen and detailed information on the condition of neointimal stent coverage (NSC) and thrombus.^6,7,8 This imaging modality has the advantage of allowing the identification of an intracoronary thrombus.⁸ Presently, no long‐term angioscopic follow‐up data after SES implantation are available. Here we present our findings from angioscopic examination, focusing on the long‐term serial changes in the NSC, especially the uncovered stent struts, and the presence of thrombus inside the SES.     

Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy

Objective

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus‐eluting stent (SES) implantation.

Design

Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, and at 6 months and 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.

Results

The maximum NSC increased from 6 months to 2 years (1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus‐related adverse events, new thrombus formation was found in one patient (5%) at the 6‐month, and in four patients (20%) at the 2‐year follow‐up evaluations. Frequencies of thrombus inside the SES at baseline, 6 months and 2 years did not differ one from another (40%, 40% and 30%, respectively; p = NS).

Conclusions

Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not a rare phenomenon.Recently, occurrence of late stent thrombosis (LST) after drug‐eluting stent implantation has became a major clinical concern.^1,2,3 A long‐term follow‐up study demonstrated that LST occurs at a constant rate of 0.6% a year for up to 3 years after drug‐eluting stent implantation.³ Pathological investigation shows that delayed arterial healing, characterised by an incomplete endothelialisation and persistence of fibrin, has a key role in the occurrence of LST.^4,5 Moreover, a powerful predictor of LST is the existence of uncovered struts without endothelialisation.⁵ We therefore proposed the hypothesis that the uncovered struts of a sirolimus‐eluting stent (SES) remain for an extended period of time.Coronary angioscopy provides a direct visualisation of the lumen and detailed information on the condition of neointimal stent coverage (NSC) and thrombus.^6,7,8 This imaging modality has the advantage of allowing the identification of an intracoronary thrombus.⁸ Presently, no long‐term angioscopic follow‐up data after SES implantation are available. We herein present our findings as derived from angioscopic examination, focusing on the long‐term serial changes in the NSC, especially the uncovered stent struts, and the presence of thrombus inside the SES.     

Microscopic measurement of inflammation in synovial tissue: inter-observer agreement for manual quantitative, semiquantitative and computerised digital image analysis

Objectives

To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.

Methods

Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman''s Rho and intraclass correlation coefficients (ICCs).

Results

Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.

Conclusion

Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.Microscopic measurement of inflammation in synovial tissue is employed globally by centres working in the field of arthritis research.¹ Adequate and comparable synovial tissue can be safely obtained using blind‐needle biopsy or rheumatological arthroscopy.^2,3,4 In the acquired samples, various parameters may be examined, including cell populations, vascularity, cytokines and adhesion molecules. In rheumatoid arthritis (RA), many of these have been found to relate to disease activity, severity, outcome, and to exhibit a change after treatment with corticosteroids, disease‐modifying antirheumatic drugs (DMARDs) and biological therapy.^{5,6,7,8,9,10,11,12,13,14,15}Several analysis techniques have been employed to measure these parameters. Semiquantitative analysis is a relatively quick method and therefore may facilitate examining large quantities of tissue.⁷ Quantitative analysis is time‐consuming but more sensitive than semiquantitative scoring to change in individual patients.¹⁶ It has been shown in previous studies that these methods can reflect overall joint inflammation when applied to relatively limited amounts of synovial tissue, even though inflammation may differ widely between individual sites in a single joint.^17,18,19 Computerised digital image analysis has been applied more recently in this area and has been shown to correlate well with conventional methods of measurement.^20,21,22This multi‐centre study was undertaken to standardise and validate the methods mentioned previously by evaluating inter‐observer agreement between multiple examiners in the measurement of selected parameters of inflammation in RA synovial tissue by manual quantitative, semiquantitative and computerised image analysis.     

Troponin-I concentration 72 h after myocardial infarction correlates with infarct size and presence of microvascular obstruction

Objectives

The aim of this study was to use late gadolinium hyper‐enhancement cardiac magnetic resonance (LGE‐CMR) imaging to determine if a 72‐h troponin‐I measurement would provide a more accurate estimation of infarct size and microvascular obstruction (MVO) than serial creatine kinase (CK) or early troponin‐I values.

Methods

LGE‐CMR was performed 3.7±1.4 days after medical treatment for acute ST elevation or non‐ST elevation myocardial infarction. Infarct size and MVO were measured and correlated with serum troponin‐I concentrations, which were sampled 12 h and 72 h after admission, in addition to serial CK levels.

Results

Ninety‐three patients, of whom 71 had received thrombolysis for ST elevation myocardial infarction, completed the CMR study. Peak CK, 12‐h troponin‐I, and 72‐h troponin‐I were related to infarct size by LGE‐CMR (r = 0.75, p<0.0001; r = 0.56, p = 0.0003; r = 0.62, p<0.0001 respectively). Serum biomarkers demonstrated higher values in the group with MVO compared with those without MVO (Peak CK 3085±1531 vs 1471±1135, p<0.001; 12‐h troponin‐I 58.3±46.9 vs 33.4±40.0, p = 0.13; 72‐h troponin‐I 11.5±9.9 vs 5.5±4.6, p<0.005). The correlation between the extent of MVO and 12‐h troponin‐I was not significant (r = 0.16), in contrast to the other serum biomarkers (peak CK r = 0.44, p<0.0001; 72‐h troponin‐I r = 0.46, p = 0.0002).

Conclusion

A single measurement of 72‐h troponin‐I is similar to serial CK measurements in the estimation of both myocardial infarct size and extent of MVO, and is superior to 12‐h troponin‐I measurements.Prognosis after acute myocardial infarction is closely related to the extent of myocardial damage. The degree of damage can be estimated by serological testing and non‐invasive imaging methods (such as echocardiography). Measurement of cytosolic enzymes such as creatine kinase (CK) and the isoenzyme CK‐MB is still common clinical practice.¹ However, the utility of these markers in determining infarct size is limited by the requirement for multiple sampling to determine the peak values or area under the curve, and their lack of specificity for myocardial damage.²Twelve‐hour serum troponin measurements are routinely used in the diagnosis of myocardial ischaemia or infarction. Although such measurements are highly specific for myocardial damage, they may provide unreliable estimates of infarct size.³ Troponin is a structural protein of the contractile apparatus which is released into the circulation in a biphasic fashion after acute myocardial infarction (AMI). An initial peak occurs in the first 24 h, due to release from the cytosolic pool. While this peak provides a reliable marker of infarct size in an animal model of non‐reperfused infarction,⁴ the complex release kinetics result in a high variability in early troponin concentrations following reperfusion therapy.²In AMI, the presence of microvascular obstruction (MVO) could cause impaired wash‐out of cardiac biomarkers in the early phase, so that the acute concentrations may not accurately reflect the true extent of myocardial damage. A second phase of troponin release occurs after 72 h, resulting from intramyocardial protein degradation,⁵ and this “plateau” value seems to be relatively unaffected by early reperfusion therapy.² The troponin concentration at 72 h may therefore be less affected by release kinetics and coronary reperfusion, and hence provide a more reliable method to quantify myocardial damage and predict the presence of MVO.Cardiac magnetic resonance (CMR) can be used to image both acute and chronic myocardial infarction using the technique of late gadolinium hyper‐enhancement (LGE).^6,7 Several animal studies have validated this technique,^8,9 and in the canine model CMR quantification of infarct size has been shown to correlate closely (r = 0.99) with histological measurements using triphenyltetrazolium chloride staining.¹⁰ Areas of severe MVO within the infarct core can also be demonstrated by LGE‐CMR in man.¹¹ The high spatial resolution of the LGE‐CMR technique allows accurate measurement of in vivo infarct size.The aim of this study was to determine if a 72 h troponin (72‐h troponin‐I) measurement would provide a more accurate estimation of infarct size than serial CK or early troponin values.     

Comparison of in vitro-specific blood tests with tuberculin skin test for diagnosis of latent tuberculosis before anti-TNF therapy

Introduction

Latent tuberculosis infection (LTBI) is detected with the tuberculin skin test (TST) before anti‐TNF therapy. We aimed to investigate in vitro blood assays with TB‐specific antigens (CFP‐10, ESAT‐6), in immune‐mediated inflammatory diseases (IMID) for LTBI screening.

Patients and methods

Sixty‐eight IMID patients with (n = 35) or without (n = 33) LTBI according to clinico‐radiographic findings or TST results (10 mm cutoff value) underwent cell proliferation assessed by thymidine incorporation and PKH‐26 dilution assays, and IFNγ‐release enzyme‐linked immunosorbent spot (ELISPOT) assays with TB‐specific antigens.

Results

In vitro blood assays gave higher positive results in patients with LTBI than without (p<0.05), with some variations between tests. Among the 13 patients with LTBI diagnosed independently of TST results, 5 had a negative TST (38.5%) and only 2 a negative blood assays result (15.4%). The 5 LTBI patients with negative TST results all had positive blood assays results. Ten patients without LTBI but with intermediate TST results (6–10 mm) had no different result than patients with TST result ⩽5 mm (p>0.3) and lower results than those with LTBI (p<0.05) on CFP‐10+ESAT‐6 ELISPOT and CFP‐10 proliferation assays.

Conclusion

Anti‐TB blood assays are beneficial for LTBI diagnosis in IMID. Compared with TST, they show a better sensitivity, as seen by positive results in 5 patients with certain LTBI and negative TST, and better specificity, as seen by negative results in most patients with intermediate TST as the only criteria of LTBI. In the absence of clinico‐radiographic findings for LTBI, blood assays could replace TST for antibiotherapy decision before anti‐TNF.TNFα blocker agents are approved for the treatment of immune‐mediated inflammatory diseases (IMID) and provide marked clinical benefit. However, they can reactivate tuberculosis (TB) infection in patients previously exposed to TB bacilli.^1,2 The presence of quiescent mycobacteria defines latent TB infection (LTBI).^3,4 Thus, screening for LTBI is necessary before initiating therapy with TNF blockers.⁵ However, to date, no perfect gold standard exists for detecting LTBI, and tuberculin skin test (TST) remains largely used. The recommendations for detecting LTBI differ worldwide.^3,6,7 In France, recommendations were established in 2002 by the RATIO (Research Axed on Tolerance of Biotherapies) study group for the Agence Française de Sécurité Sanitaire des Produits de Santé.^8,9 Patients are considered to have LTBI requiring treatment with prophylactic antibiotics before starting anti‐TNFα therapy if they had previous TB with no adequate treatment, tuberculosis primo‐infection, residual nodular tuberculous lesions larger than 1 cm³ or old lesions suggesting TB diagnosis (parenchymatous abnormalities or pleural thickening) as seen on chest radiography or weals larger than 10 mm in diameter in response to the TST. Adequate anti‐TB treatment was defined as treatment initiated after 1970, lasting at least 6 months and including at least 2 months with the combination rifampicin–pyrazinamide. The choice of the threshold of 10 mm for the TST result was established in 2002 in France since the programme of vaccination with bacille Calmette–Guérin (BCG) was mandated in France, and nearly 100% of the population has been vaccinated. Nevertheless, after July 2005, the threshold was decreased to 5 mm as in most of all other countries.¹⁰The TST is the current method to detect LTBI but has numerous drawbacks. Indeed, the TST requires a return visit for reading the test result. It has a poor specificity, since previous BCG vaccination and environmental mycobacterial exposure can result in false‐positive results in all subjects.^6,11,12 This poor specificity can lead to unnecessary treatment with antibiotics, with a significant risk of drug toxicity.^13,14,15 On the other hand, TST in IMID may often give a more negative reaction than in the general population, mainly because of the disease or immunosuppressive drug use.^16,17 This poor sensitivity can lead to false‐negative results, with a subsequent risk of TB reactivation with anti‐TNF therapy.The identification of genes in the mycobacterium TB genome that are absent in BCG and most environmental mycobacteria offers an opportunity to develop more specific tests to investigate Mycobacterium tuberculosis (M. tuberculosis) infection, particularly LTBI.¹⁸ Culture fibrate protein‐10 (CFP‐10) and early secretory antigen target‐6 (ESAT‐6) are two such gene products that are strong targets of the cellular immune response in TB patients. In vivo‐specific T‐cell based assay investigating interferon gamma (IFNγ) release or T‐cell proliferation in the presence of these specific mycobacterial antigens could be useful in screening for LTBI before anti‐TNF therapy. New IFNγ‐based ex vivo assays involving CFP‐10 and ESAT‐6 (T‐SPOT TB, Oxford Immunotec, Abingdon, UK) and QuantiFERON TB Gold (QFT‐G; Cellestis, Carnegie, Australia) allow for diagnosis of active TB, recent primo‐infection or LTBI.¹² These tests seem to be more accurate than the TST for this purpose in the general population.¹² To date, the performance of the commercial assays in detecting LTBI in patients with IMID receiving immunosuppressive drugs has not been demonstrated, and the frequency of indeterminate results is still debated.^19,20,21We aimed to investigate the performance of homemade anti‐CFP‐10 and anti‐ESAT‐6 proliferative and enzyme‐linked immunosorbent spot (ELISPOT) assays in detecting LTBI in patients with IMID before anti‐TNFα therapy. We analysed two subgroups of patients: those with confirmed LTBI independent of TST result, and those with LTBI based exclusively on a positive TST result between 6 and 10 mm.