Selective immunomodulation in patients with inflammatory bowel disease—future therapy or reality?

Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohn's disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor- α (TNF-α). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administred cyclosporine is able to improve the disease activity in ulcerative colitis and Crohn's disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-Ira) competitively binds to the IL-1 receptor located on several lymphocytes. Treatment of animals with IL-Ira has been successful and clinical trials using recombinant IL-1ra are underway in IBD. Antibodies against αIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of α-interferon seems to be effective in some patients with Crohn's disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohn's disease. TNF-α shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohn's disease, the effects of the administration of antibodies to TNF-α were excellent.     

Which patients with heart failure should receive specialist palliative care?

Aims

We investigated which patients with heart failure (HF) should receive specialist palliative care (SPC) by first creating a definition of need for SPC in patients hospitalised with HF using patient‐reported outcome measures (PROMs) and then testing this definition using the outcome of days alive and out of hospital (DAOH). We also evaluated which baseline variables predicted need for SPC and whether those with this need received SPC.

Methods and results

PROMs assessing quality of life (QoL), symptoms, and mood were administered at baseline and every 4 months. SPC need was defined as persistently severe impairment of any PROM without improvement (or severe impairment immediately preceding death). We then tested whether need for SPC, so defined, was reflected in DAOH, a measure which combines length of stay, days of hospital re‐admission, and days lost due to death. Of 272 patients recruited, 74 (27%) met the definition of SPC needs. These patients lived one third fewer DAOH than those without SPC need (and less than a quarter of QoL‐adjusted DAOH). A Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score of <29 identified patients who subsequently had SPC needs (area under receiver operating characteristic curve 0.78). Twenty‐four per cent of patients with SPC needs actually received SPC (n = 18).

Conclusions

A quarter of patients hospitalised with HF had a need for SPC and were identified by a low KCCQ score on admission. Those with SPC need spent many fewer DAOH and their DAOH were of significantly worse quality. Very few patients with SPC needs accessed SPC services.     

Do patients with inflammatory bowel disease want genetic testing?

BACKGROUND: Inflammatory bowel disease (IBD) is a complex genetic disorder characterized by nonmendelian inheritance, incomplete penetrance, and disease susceptibility but not disease certainty. Genotype and phenotype associations are described, but the level of interest of patients with IBD in genetic testing for themselves or at-risk family members remains unknown. Thus, the goal of this study was to assess the interest of patients with IBD in genetic testing and their willingness to accept the uncertainty inherent in complex genetics. MATERIALS AND METHODS: Consecutive outpatients with IBD were recruited to complete a 57-item self-administered survey. The survey included a layperson explanation of the limits of IBD genetics. A 5-point Likert scale was used to determine willingness to undergo genetic testing to determine diagnosis, prognosis, and treatment; to help their family; and to advance medical knowledge. The IBD Questionnaire, a validated measure of the health status attitudes of patients with IBD, was used. To determine limits of patient interest in testing family members, the standard reference gamble paradigm was used. Patients were presented with situations for the genetic test with various levels of certainty in 10% decrements starting with 100%. They indicated the lowest degree of certainty that they would accept to test their family member. RESULTS: One hundred fourteen patients (mean age 38.4 years; 48.2% women) completed the survey. Of these 114, 71.9% (82) had Crohn's disease. Among the patients who answered questions on self-willingness, 76.8% (86 of 112) would undergo testing for diagnostic confirmation, 81.3% (91 of 112) for prognostic value, 88.4% (99 of 112) for therapeutic decision making, and 85.0% (96 of 113) for advancement of medical knowledge. We found that 28.1% of patients (32 of 114) had a first-degree relative with IBD. Those patients with a first-degree relative with IBD were more willing to undergo genetic testing than those without a first-degree relative with IBD (raw score on self-willingness 4.62 vs 4.36; P=0.026). There was no significant association between patients' health status and their willingness to undergo genetic testing (IBD Questionnaire score and raw score on self-willingness; Spearman's correlation coefficient -0.06; P=0.51). We also found that 88.6% of patients (93 of 105) indicated an interest in testing family members if the test provided absolute certainty of future disease. The average lowest level of certainty these patients were willing to accept was 42.2%. CONCLUSIONS: Despite the complexity of IBD genetics, most patients with IBD are interested in testing and willing to accept a variable degree of uncertainty about the results. An important minority of patients does not wish to be tested. Future work should better identify the reasons for these different attitudes. This information should be factored into plans for widespread clinical testing.     

Are patients with inflammatory bowel disease receiving optimal care?

OBJECTIVES: Guidelines have been published as a framework for therapy of patients with inflammatory bowel disease (IBD). The purpose of this study was to determine whether patients referred for a second opinion were receiving therapy in accordance with practice guidelines. METHODS: Patients with luminal IBD under the care of a gastroenterologist who sought a a second opinion at Brigham and Women's Hospital between January 2001 and April 2003 were enrolled in this study. Clinical information was obtained by direct patient interview at the time of initial patient visit and by a review of prior records. Data obtained included the diagnosis, clinical symptoms, prior medical therapy, preventive measures for metabolic bone disease, and colon-cancer screening. RESULTS: The study population consisted of 67 consecutive patients: 21 with ulcerative colitis, 44 with Crohn's disease and 2 in whom the diagnosis of IBD could not be confirmed. Of the 65 patients with confirmed IBD, 56 patients had symptoms of active disease and 9 were asymptomatic. All analyses were carried out on the 56 patients with active disease. Of the 33 patients treated with aminosalicylates, 21 (64%) were not receiving maximal doses. Nine of 12 (75%) patients with distal ulcerative colitis were not receiving rectal aminosalicylate therapy. Within 6 months of their clinic visit, 35 patients had received corticosteroid therapy, and 27 (77%) patients had been treated with corticosteroids for greater than 3 months. In 16 of 27 (59%) there was no attempt to start steroid sparing medications such as 6-mercaptopurine (6MP), azathioprine, or infliximab. Of the 11 patients treated with either 6MP or azathioprine, 9 (82%) were suboptimally dosed without an attempt to increase dosage. Of the 27 patients on prolonged corticosteroid therapy 21 (78%) received inadequate treatment to prevent metabolic bone disease. Three of 9 patients (33%) meeting indications for surveillance colonoscopy for dysplasia had not undergone colonoscopy at the appropriate interval. CONCLUSIONS: Patients with IBD often do not receive optimal medical therapy. In particular, there is suboptimal dosing of 5-ASA and immunomodulatory medications, prolonged use of corticosteroids, failure to use steroid-sparing agents, inadequate measures to prevent metabolic bone disease, and inadequate screening for colorectal cancer.     

Which patients with unprovoked VTE should receive extended anticoagulation? the minority

Venous thromboembolism (VTE) is associated with a long term risk of recurrence. This risk is at least in part related to the presence of major identifiable risk factors at the time of the index event. It is generally low in the presence of removable risk factors, and very high in the presence of permanent risk factors such as active cancer. This categorization is important because it drives the duration of secondary prevention treatment with anticoagulant drugs. Unfortunately, up to 40–50% of VTE events remain classified as unprovoked. This large group of patients is obviously heterogeneous, with an unpredictable risk of recurrence. Evidences from clinical trials suggest that extending secondary prevention with vitamin K antagonists (VKAs) for 1 or 2 years after an initial course of treatment in patients with unprovoked VTE does not provide additional benefit in terms of reducing the long term risk of recurrence. Prolonging indefinitely the duration of treatment would likely be effective in reducing this risk, but at the cost of unnecessarily expose the majority of patients to several complications, there including major bleeding events, and inconveniences. A number of variables have been identified to predict the individual risk of recurrence in these patients and some clinical prediction rules have been proposed. Improved patients stratification, together with a better understanding of the mechanisms underlying unprovoked VTE, should allow physicians to individually tailor the optimal duration of secondary prevention and to identify those patients (likely the minority) for whom indefinite duration of treatment is warranted.     

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

In the last 15 years the management of inflammatory bowel disease has evolved greatly,largely through the increased use of immunomodulators and,especially,anti-tumor necrosis factor(anti-TNF) biologic agents. Within this time period,confidence in the use of anti-TNFs has increased,whilst,especially in recent years,the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines,combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease,especially those who are recently diagnosed. Concurrently,therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and antiTNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent,or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also,however there are few data to support this. Similarly,the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention,including post hoc analyses of the pivotal registration trials,has focused on the optimization of anti-TNF agents,when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy,including an evaluation of recent data addressing unanswered questions regarding the optimal timing,dosage and duration of immunomodulator therapy in combination therapy patients.     

Should patients with hypertension receive antithrombotic therapy?

The main complications of hypertension, i.e. coronary heart disease, ischaemic strokes and peripheral vascular disease (PVD), are usually related to thrombosis. Increasing evidence also suggests that hypertension fulfils the components of Virchow's triad, thus conferring a prothrombotic or hypercoagulable state, as evident by abnormalities of haemostasis, platelets and endothelial function. It therefore seems plausible that use of antithrombotic therapy may help prevent these thrombosis-related complications of hypertension. Indeed, hypertensive patients with an estimated 10-year CHD risk > or = 15% will have their cardiovascular risk reduced by 25% using antihypertensive treatment, but the addition of aspirin further reduces major cardiovascular events by 15%. Recent guidelines recommend the use of aspirin 75 mg daily for hypertensive patients who have no contraindication to aspirin, in one of the following categories: (i) secondary prevention - cardiovascular complications (myocardial infarction, angina, non-haemorrhagic stroke, peripheral vascular disease or atherosclerotic renovascular disease); and (ii) primary prevention - those with blood pressure controlled to < 150/90 mmHg and one of: (a) age > or = 50 years and target organ damage (e.g. LVH, renal impairment, or proteinuria); (b) a 10-year CHD risk > or = 15%; or (c) type II diabetes mellitus. However, some of the risks of aspirin administration, namely increased incidence of major bleeding events, may possibly outweigh the benefits, especially in low-risk individuals.     

Which diabetic patients should receive podiatry care? An objective analysis

INTRODUCTION: Diabetes is the leading cause of lower limb amputation in Australia. However, due to limited resources, it is not feasible for everyone with diabetes to access podiatry care, and some objective guidelines of who should receive podiatry is required. METHODS: A total of 250 patients with neuropathy (Biothesiometer; Biomedical Instruments, Newbury, Ohio, USA) ( > 30, age < 65)) but no active foot lesion, and 222 without neuropathy matched for age, type of diabetes, gender and duration, was followed prospectively for 2 years. Sensation was also tested using a 10 g Semmes Weinstein monofilament (Royal Prince Alfred Hospital Diabetes Centre). After the baseline examination, patients were contacted at 6 months and thereafter yearly to determine ulcer status. Incidence of foot ulceration across different risk categories was calculated using Kaplan-Meier survival curve. Log-rank test and Cox's proportional model were used to compare groups. The Number Needed to Treat (NNT) to prevent one ulcer per year was calculated using the standard formulae. RESULTS: During the follow-up period, 34 new ulcers occurred in the neuropathy group and three ulcers in the control group (chi2 (1df) = 21.3; P < 0.0001), equating to an annual incidence of 6.3% and 0.5%, respectively. Fifty-four per cent of the ulcers were due to trauma from footwear. Further stratification of the neuropathy group showed annual incidence of ulceration to be 4% for those with abnormal biothesiometer reading, but who could still feel the monofilament, 10% for those who cannot feel the monofilament and 26% for those with previous ulceration or amputation. Predictors of ulceration were past history of ulceration/amputation (chi2 = 27.8; P < 0.0001) and the presence of neuropathy (chi2 = 4.7; P = 0.03). Assuming a 55% relative risk reduction in ulceration from podiatry care (mean of estimates from 10 reports), the NNT to prevent one foot ulcer per year was: no neuropathy (vibration perception threshold (VPT) < 30)), NNT = 367; neuropathy (VPT > 30) alone, NNT = 45; +cannot feel monofilament, NNT = 18; +previous ulcer/amputation, NNT = 7. CONCLUSION: Provision of podiatry care to diabetic patients should not be only economically based, but should also be directed to those with reduced sensation, especially where there is a previous history of ulceration or amputation.     

Laparoscopic adult colorectal surgeon and adolescents with inflammatory bowel disease: a safe combination?

Introduction  

A multidisciplinary tertiary service for adolescents with inflammatory bowel disease (IBD) was commenced in April 2008, aiming to provide specialist treatment for adolescent patients and bridge the gap between existing paediatric and adult surgical services. A single laparoscopic colorectal surgeon who normally treats adult patients has been part of the multidisciplinary team since its inception.