Severe ulcerative colitis: present medical treatment strategies

A total of 15 – 19% of ulcerative colitis patients have a severe attack at some time during their illness. As a consequence of its high associated mortality and morbidity rates, a close collaboration between gastroenterologists and surgeons in their management is mandatory, in order to define, as best as possible, the timing of surgery (i.e., colectomy) when patients fail to respond to medical treatment or worsen despite optimal medical treatment. The first step in medical treatment consists of using intravenous corticosteroids as they have been demonstrated to reduce drastically the mortality rates. However, at 1 year approximately 25% of patients become corticosteroid dependent and 30% require colectomy, which can consistently affect their quality of life. Therefore, intravenous ciclosporin has been proposed as a rescue therapy, with a further improvement of short-term efficacy and reduction of surgery requirement. Nevertheless, its use is associated with a risk of toxicity and intravenous ciclosporin is not easy to use in non-specialised centres. In addition, long-term studies suggest that colectomy is often only delayed and relapse frequent. Consequently, some authors evaluate the potential use of infliximab. Available data are encouraging, reporting a significant short-term reduction in colectomy rate. Nevertheless, additional trials are required to better define the more effective and safe treatment option(s), for both the short- and long-term, in this patient setting; a question addressed in ongoing trials.     

Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe,steroid-refractory ulcerative colitis

BACKGROUND: Intravenous ciclosporin is considered to be the only alternative to avoid surgery in severe, steroid-refractory ulcerative colitis. In responders, some authors recommend a switch to oral ciclosporin to act as a 'bridge' until the therapeutic action of azathioprine is achieved for maintenance treatment. AIM: To report the short- and long-term outcome of intravenous ciclosporin-responsive ulcerative colitis patients treated with oral azathioprine without oral ciclosporin. METHODS: The records of all patients treated with intravenous ciclosporin for severe, steroid-refractory ulcerative colitis were reviewed. Responders following treatment with azathioprine but without oral ciclosporin as maintenance therapy were included. Patients with colonic cytomegalovirus infection and/or follow-up of less than 1 year were excluded. RESULTS: Twenty-seven patients were included. Steroids were discontinued in 24 (89%). The median follow-up was 36 months. Eighteen (75%) patients presented mild or moderate relapses, which were easily managed with salicylates or steroids. Cumulative probabilities of relapse were 42%, 72% and 77% at 1, 3 and 5 years, respectively. Eleven (40.7%) patients underwent elective colectomy. Cumulative probabilities of colectomy were 29%, 35% and 42% at 1, 3 and 5 years, respectively. No opportunistic infections were observed. CONCLUSIONS: Oral azathioprine seems to be enough to maintain long-term remission induced by intravenous ciclosporin in patients with steroid-refractory ulcerative colitis. The 'bridging step' with oral ciclosporin may not be necessary in this subset of patients, although a randomized controlled trial is warranted to confirm this hypothesis.     

Long-term results of low-dose intravenous ciclosporin for acute severe ulcerative colitis

BACKGROUND: Intravenous ciclosporin for acute, severe colitis is usually administered in a dose of 4 mg/kg/day, with concurrent intravenous steroids. This is associated with considerable morbidity. We have been using a low-dose regimen, most commonly without concurrent steroids, for seven years, and present the outcome. METHODS: Records of all patients admitted for severe ulcerative colitis, treated by one physician over seven years, were reviewed. RESULTS: Thirty-one patients received low-dose intravenous ciclosporin (2 mg/kg/day) for a median 8 days. Eleven early patients received concurrent intravenous corticosteroids. Three patients had hypertension requiring dose reduction, one elevated creatinine and one elevated liver enzymes (all transient), and four experienced infection (two arm cellulitis, one perianal abscess, one post-operative wound infection). Twenty-four patients (77%) avoided urgent colectomy, and were discharged on oral ciclosporin and azathioprine. After a median 18 months (range 3-77), 14 patients (45% of total) avoided colectomy, of whom eight had flares responding to medical therapy and two had persistent, mildly active disease. CONCLUSIONS: Low-dose intravenous ciclosporin (2 mg/kg/day), usually used as a monotherapy and followed by azathioprine, achieves similar long-term efficacy to higher dose ciclosporin combined with steroids in severe acute ulcerative colitis. Morbidity appears to be low.     

Review article: the optimal medical management of acute severe ulcerative colitis

Aliment Pharmacol Ther 2010; 32: 615–627

Summary

Background Management of acute severe ulcerative colitis (UC) is a clinical challenge, with a mortality rate of approximately 1–2%. The traditional management with intravenous corticosteroids has been modified by introduction of ciclosporin and more recently, infliximab. Aim To provide a detailed and comprehensive review of the medical management of acute severe UC. Methods PubMed and recent conference abstracts were searched for articles relating to treatment of acute severe UC. Results Two‐thirds of patients respond to intravenous steroids in the short term. In those who fail steroids, low‐dose intravenous ciclosporin at 2 mg/kg/day is effective. Approximately 75% and 50% of patients treated with ciclosporin avoid colectomy in the short and long‐terms, respectively. Long‐term outcome of ciclosporin therapy is improved by introduction of azathioprine on discharge from hospital, together with oral ciclosporin as a bridging therapy. Controlled data show that infliximab is effective as rescue therapy for acute severe UC and the effect appears to be durable, although longer‐term follow‐up data are needed. Conclusions Both ciclosporin and infliximab have demonstrated efficacy as rescue medical therapies in patients with acute severe UC, but surgery needs to be considered if there is failure to improve or clinical deterioration.     

Steroid-refractory severe ulcerative colitis: what are the available treatment options?

Approximately 15% of patients with ulcerative colitis will experience a severe episode requiring hospitalization. Although intravenous corticosteroids are the current first-line therapy for these patients, about 30% of patients do not respond to corticosteroids and require either an alternative anti-inflammatory agent or surgery. Ciclosporin has proven its efficacy in a number of controlled trials in this setting and is characterized by high early response rates. Patients who respond to ciclosporin and avoid colectomy are more likely to retain their colon if they bridge to immunomodulators in the medium term. Infliximab has also demonstrated efficacy in reducing early colectomy rates and longer term data are awaited. Other agents, such as tacrolimus and basiliximab, and leukocytapheresis, have been studied in small trials and may be alternative options. Key issues remain as to what should be first- and second-line therapies, when surgery should be undertaken, and the risk of switching between immunosuppressants in these critical patients.     

Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study

Aliment Pharmacol Ther 2012; 35: 275–283

Summary

Background Ciclosporin has proven to be effective in patients with corticosteroid‐refractory ulcerative colitis (UC). When therapy with this drug fails, infliximab can be considered to avoid colectomy. The efficacy and safety of this sequential approach remain unknown. Aim To assess the efficacy and safety profile of treatment with infliximab after failure of ciclosporin in patients with a corticosteroid‐refractory flare of UC. Methods Retrospective review of medical records of patients with a corticosteroid‐refractory flare of UC who did not respond to ciclosporin and received salvage therapy with infliximab within a month of discontinuing ciclosporin. The severity of the flare and response to the treatment were graded using the Lichtiger index. Cumulative rates of colectomy were calculated using Kaplan–Meier analysis. Cox regression analysis was performed to identify predictors of colectomy. To evaluate the safety profile of this treatment strategy, any adverse event occurring after the first infusion of infliximab was considered. Results The study population comprised 47 patients with corticosteroid‐refractory UC treated with infliximab after failure of ciclosporin. The median baseline Lichtiger index was 13. The mean time from the last ciclosporin dose to the first infliximab infusion was 6 days. After the first infliximab infusion, 13% of patients achieved remission, and 74% partial response. Of the 35 patients who received the third infliximab infusion, 60% achieved remission, and 37% partial response. Fourteen patients (30%) underwent colectomy. The rate of adverse events was 23%. One death occurred in a 40‐year‐old man who failed ciclosporin and infliximab and underwent surgery 10 days after the first infliximab infusion; he died of nosocomial pneumonia. Conclusions Treatment with infliximab makes it possible to avoid colectomy in two‐thirds of corticosteroid‐refractory UC patients in whom ciclosporin fails. However, the rates of adverse events and mortality mean that the decision to administer sequential therapy (ciclosporin–infliximab) should be taken on an individual basis.     

Review article: how and when to use ciclosporin in ulcerative colitis

Although colectomy for ulcerative colitis is curative, long-term quality of life is reduced. Intravenous ciclosporin 4 mg/kg/day has significant toxicity. There is now evidence that low-dose ciclosporin (2 mg/kg daily by intravenous infusion, or 5-6 mg/kg daily in a twice daily oral dosage) has an acceptable safety profile, even when used in combination with corticosteroids. Drug dosage should be adjusted to the levels of 150-250 ng/mL initially (random levels during intravenous infusion, or trough levels for oral use). Ciclosporin should be considered not only in those who have failed 7 days of corticosteroids, but also in fulminant colitis at day 3, if not responding to corticosteroids. The drug should be avoided in frail or elderly patients with significant comorbidity, and also where colectomy is likely to be necessary in the short to medium term. Ciclosporin should not be continued for more than 7 days, unless there is a definite response. A 70-80% initial response is likely, and responders are discharged on oral ciclosporin, adding thiopurines and tailing prednisolone rapidly. The drug should be continued for 3 months. The likelihood of avoiding colectomy over 2-3 years is 40-50%. More studies are needed to evaluate the use of oral ciclosporin in corticosteroid-refractory colitis in out-patients, and to assess whether monotherapy (without corticosteroids) is significantly safer, without loss of efficacy.     

Belatacept

Immunosuppressive therapy designed to prevent kidney graft rejection usually consists of a triple-drug combination including a corticosteroid, a calcineurin inhibitor (ciclosporin or tacrolimus) and a drug that inhibits cell proliferation (azathioprine or mycophenolate mofetil). Belatacept is closely related to abatacept, an immunosuppressant marketed for rheumatic diseases. It is now authorised in the European Union for the prevention of kidney graft rejection, as a replacement for the calcineurin inhibitor. Two randomised controlled trials compared belatacept (2 doses) versus ciclosporin as part of the immunosuppressive regimen in respectively 666 and 534 patients. After 3 years of follow-up, survival with a functioning graft did not differ between the groups (about 80% in the trial closest to European protocols). Only the use of a high dose of belatacept instead of ciclosporin resulted in better preservation of renal function, but this is not the authorised dose. Lymphomas, particularly those affecting the central nervous system, were more frequent with belatacept in both trials (1.4% versus 0.9%). The risk was particularly high in patients receiving the high dose of belatacept, and in patients who were seronegative for Epstein-Barr virus. Overall, the risk of infections seems to be similar with belatacept and ciclosporin, but certain severe infections were more frequent with belatacept, including progressive multifocal leukoencephalopathy and tuberculosis. Unlike ciclosporin, belatacept plasma concentrations do not need to be monitored. However, intravenous belatacept administration is less convenient than oral ciclosporin administration, especially during long-term treatment. Overall, it is better to continue to use ciclosporin, a better-documented drug, as part of immunosuppressive therapy after kidney transplantation.     

Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis

BACKGROUND: Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication. METHODS: Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long-term immunosuppression. RESULTS: All patients responded within 1-2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side-effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side-effects were common. CONCLUSION: Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid-refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side-effects.     

The use of ciclosporin in paediatric inflammatory bowel disease: an Italian experience

AIM: To asses the efficacy and safety of ciclosporin in a paediatric population with inflammatory bowel disease. PATIENTS AND METHODS: Twenty-three Italian children treated with ciclosporin were studied retrospectively. The indications for treatment were severe unresponsive colitis, chronic active colitis or severe fistulizing Crohn's disease. The treatment duration, follow-up and causes of drug discontinuation were assessed. RESULTS: Sixteen patients were treated intravenously for a mean time of 10 +/- 7 days (1-24 days) and 19 orally for a mean time of 133 days (17-660 days). The mean follow-up of all patients was 13.2 months. Ciclosporin was totally ineffective, being discontinued for surgery, in nine of 23 patients (39%); it was discontinued for partial response in three patients (13%). During treatment, clinical remission was achieved in eight children (35%) and maintained after drug withdrawal in four (17%). In severe unresponsive colitis, urgent colectomy was avoided in 12 (85%) of 14 patients who tolerated the drug. Side-effects appeared in six of 23 patients (26%), and three (13%) required ciclosporin to be discontinued due to neurotoxicity. CONCLUSIONS: Ciclosporin shows disappointing long-term results in the treatment of refractory inflammatory bowel disease, but can play an important role in preventing urgent surgery in unresponsive severe colitis. Severe side-effects can occur.     

Does anti-TNF therapy reduce the requirement for surgery in ulcerative colitis? A systematic review

Infliximab has demonstrated its efficacy in moderate to severe ulcerative colitis. The Active Ulcerative Colitis Trial (ACT) -1 and 2 have demonstrated the beneficial impact of infliximab on the short-term colectomy rate. However, data evaluating this outcome beyond one year remains scarce. To provide evidence on the potential impact of infliximab on the long-term colectomy rate in patients suffering from ulcerative colitis, data was reviewed from randomized and controlled studies, referral centre studies and population-based studies, in adult and pediatric populations. In the pre-biologic era, 9-33%, 50% and 29% of adult patients with ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts, respectively. In the pediatric population, 9-61% and 8-20% underwent colectomy in referral centers and population-based cohorts, respectively. Between 10 and 36% of adult patients treated with infliximab for ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts. In the pediatric population treated with infliximab, long-term data is lacking, with colectomy rates ranging from 16 to 28%. Whether infliximab proves to be a disease modifying treatment in ulcerative colitis in the long term remains to be elucidated and will require further long-term prospective studies.     

Ciclosporin aerosol in lung transplantation

The development of ciclosporin as an aerosol for rejection immunosuppression following lung transplantation started as a research idea at the University of Pittsburgh in 1989. In the 17 subsequent years, the development of the aerosol, testing in animals and several protocols testing the drug in patients have all taken place at the University of Pittsburgh and State University of New York. No other medical advances have displaced the potential of the drug during this time in lung transplantation, which still has a dismal 5-year survival of 50%. Therefore, the recent publication of the double-blind, placebo-controlled study of aerosolised ciclosporin for long-term use to significantly improve patient survival was heralded as a breakthrough by the commentary in the New England Journal of Medicine. Nevertheless, multiple problems may prevent this drug from ever receiving FDA approval and reaching the market. These problems include the need for a multi-centre study, a lack of surrogate markers for chronic rejection in lung transplant patients and a drug formulation that will prevent the expansion of the use of aerosolised ciclosporin for other indications.     

Low-dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis

BACKGROUND: The optimal modalities of treatment with oral microemulsion ciclosporin in patients with severe, steroid-refractory ulcerative colitis are uncertain. AIM: To assess the applicability, in terms of efficacy and tolerability, of a standard oral microemulsion ciclosporin treatment protocol targeting relatively low blood ciclosporin concentrations, in patients with severe, steroid-resistant ulcerative colitis. PATIENTS AND METHODS: Patients with a severe attack of ulcerative colitis and no satisfactory response to intravenous corticosteroids were started on oral microemulsion ciclosporin. Dosages were adapted according to a standard protocol, targeting a blood predose ciclosporin concentration (C0) of 100-200 ng/mL. Patients without a clinical response on day 8 were scheduled for colectomy. RESULTS: Sixteen patients were enrolled. A clinical response was observed in 14/16 (88%). The mean clinical activity index scores and concentrations of C-reactive protein on days 0, 4 and 8 were 11.8, 6.7 and 4.1, and 50.3, 19.3 and 9.7 mg/L respectively. The mean C0 (days 0-8) was 149 pg/mL. The mean creatinine clearance rates on days 0 and 8 were 88 and 96 mL/min. One patient had an acute elevation of transaminases that resulted in discontinuing ciclosporin. CONCLUSIONS: Even when dosed for a target C0 of 100-200 ng/mL, oral microemulsion ciclosporin for severe, steroid-refractory ulcerative colitis achieves an efficacy similar to that attained with higher, potentially more toxic levels. The oral route should replace intravenous treatment in this clinical setting.     

Ciclosporin aerosol in lung transplantation

The development of ciclosporin as an aerosol for rejection immunosuppression following lung transplantation started as a research idea at the University of Pittsburgh in 1989. In the 17 subsequent years, the development of the aerosol, testing in animals and several protocols testing the drug in patients have all taken place at the University of Pittsburgh and State University of New York. No other medical advances have displaced the potential of the drug during this time in lung transplantation, which still has a dismal 5-year survival of 50%. Therefore, the recent publication of the double-blind, placebo-controlled study of aerosolised ciclosporin for long-term use to significantly improve patient survival was heralded as a breakthrough by the commentary in the New England Journal of Medicine. Nevertheless, multiple problems may prevent this drug from ever receiving FDA approval and reaching the market. These problems include the need for a multi-centre study, a lack of surrogate markers for chronic rejection in lung transplant patients and a drug formulation that will prevent the expansion of the use of aerosolised ciclosporin for other indications.     

Infliximab: the evidence for its place in therapy in ulcerative colitis

INTRODUCTION: Refractory ulcerative colitis has a high, unmet medical need for avoiding steroid dependency and avoiding colectomy. Controlled trials with biologic agents have recently been reported. AIMS: We aimed to review the current evidence supporting the use of the monoclonal antitumor necrosis factor antibody, infliximab, in active ulcerative colitis and determine its current place in therapy. EVIDENCE REVIEW: Although faced with initial conflicting data particularly in steroid-refractory patients, two large, placebo-controlled trials have shown that intravenous infliximab induces and maintains clinical improvement in a clinically significant proportion of patients when used with scheduled re-treatment. Infliximab also spares steroids and induces endoscopic remission in moderately ill patients. In fulminant colitis unresponsive to intravenous steroids, one placebo-controlled trial indicates that infliximab is able to prevent colectomy in this patient population. Evidence for cost effectiveness and avoidance of colectomy long term are still lacking. PLACE IN THERAPY: Infliximab 5 mg/kg induction at 0, 2, and 6 weeks, and every 8 weeks thereafter should be considered in patients with moderately to severely active ulcerative colitis failing medical therapy. Steroid-dependent and steroid-refractory patients also qualify for infliximab therapy.     

Review article: management of peptic ulcer bleeding-the roles of proton pump inhibitors and Helicobacter pylori eradication

Peptic ulcer bleeding is associated with substantial morbidity and mortality. The goals of management are to control any active bleeding and prevent re-bleeding and then to heal the ulcer and prevent its recurrence. Initial management strategies are guided by the patient's clinical condition and endoscopic findings. Thus, treatment may consist of endoscopic and medical therapy and, sometimes, surgery. Control of acid secretion, preferably with proton pump inhibitor therapy in the initial management continues to evolve; it has also been used as both an adjunct to endoscopic therapy and as primary treatment. These agents have been found to be effective in some trials in the reduction of re-bleeding and the need for surgery, although there is no clear benefit demonstrated for overall mortality. Proton pump inhibitors have been administered either intravenously or orally in different trials. The long-term management of patients with peptic ulcer, after the initial bleeding episode, should include patient stratification based upon risk factors for ulcer recurrence (i.e. Helicobacter pylori infection, use of aspirin or nonsteroidal anti-inflammatory drugs). Elimination or modification of these risk factors reduces the risk of ulcer recurrence and, hence, of recurrent ulcer bleeding.     

Intravenous streptokinase. A reappraisal of its therapeutic use in acute myocardial infarction

Streptokinase, the first of the thrombolytic agents to be used in acute myocardial infarction, has now been administered to many thousands of patients with this condition. Since early intervention and accessibility of care is paramount in these patients, intravenous infusion of streptokinase has largely replaced intracoronary use. Results of major trials (GISSI, ISIS-2 and ISAM) comparing streptokinase with standard treatment in more than 30,000 patients prove convincingly that intravenous streptokinase increases patient survival after myocardial infarction. The largest trial, ISIS-2, demonstrated a 23% reduction in 5-week vascular mortality after streptokinase use. The greatest benefits occur where streptokinase infusion is initiated early after symptom onset, although late benefit has been observed in patients treated up to 24 hours after pain onset. Importantly, mortality is further decreased by combining streptokinase with aspirin, as shown by a 53% reduction in mortality using the combination in the ISIS-2 trial. Mortality has also been reduced in trials investigating the use of the thrombolytic agents rt-PA and anistreplase. Streptokinase and rt-PA produced similar reductions in mortality in the recent GISSI-2 and International t-PA/Streptokinase Mortality trials, findings which may be further clarified by ongoing comparative trials such as ISIS-3. Reperfusion of about 50 to 60% of occluded coronary arteries occurs with intravenous streptokinase, and left ventricular function is improved. Direct comparisons with rt-PA show a superior effect for the newer agent on early reperfusion, but a similar ability to salvage myocardial function. The complexities of the relationship between reperfusion, left ventricular function and mortality constitute an area of considerable clinical interest requiring further study to clearly differentiate between the drugs available to the physician. The most common adverse events observed during intravenous streptokinase infusion are bleeding complications. An incidence of 3.6% for minor bleeding and 0.4% for major haemorrhage (requiring transfusion) is derived from the combined results of the GISSI and ISIS-2 studies. Bleeding does not appear to be more frequent or severe with intravenous streptokinase than with the more fibrin-selective agent, rt-PA. While the risk to benefit ratio of sequential heparin following streptokinase therapy remains equivocal, the adjuvant use of aspirin confers a clinical advantage over streptokinase alone. In conclusion, streptokinase has now been proven to reduce mortality in patients with acute myocardial infarction, with an acceptable risk of bleeding complications. Given the substantial data that have now accumulated with extensive clinical experience, intravenous streptokinase should be considered a first-line agent in suitable patients.     

Effects of laparoscopic surgery on survival,quality of care and utilization in patients with colon cancer: a population-based study

Objective: Laparoscopy is a safe and effective treatment for colon cancer. However, its effects on short- and long-term health outcomes and medical utilization are not fully elucidated. This study aimed to compare short- and long-term utilization and health outcomes of colon cancer patients who underwent either laparoscopic or open surgery in a population-based cohort.

Methods: This study was conducted by linking data from Taiwan Cancer Registry, National Health Insurance claims and Death Registry. Patients aged 18 and older with colon cancer between 2009 and 2012 were included in the study. Propensity score matching was used to minimize selection bias between laparoscopic and open surgery groups. Cox proportional hazard regression and generalized linear mixed logistic regression were used to test hypotheses.

Results: Among the 11,269 colon cancer patients who underwent colectomy, 3236 (28.72%) received laparoscopy and 8033 (71.28%) underwent open surgery. Patients who received laparoscopic surgery had better overall survival (HR?=?0.82; 95% CI: 0.70–0.97). These patients also had lower 30?day mortality (0.44% vs. 0.91%), lower 1 year mortality (2.83% vs. 4.68%), lower overall occurrence of complications (6.16% vs. 8.77%), shorter mean length of stay (12.53 vs. 14.93 days) and lower cost for index hospitalization (US$4325.34 vs. US$4453.90). No significant differences were observed in medical utilization over a period of 365 days after the surgery.

Conclusions: Our results demonstrate that, in both the short- and long-term post-operation periods, laparoscopic surgery reduced the likelihood of postoperative complications, 30?day, and 1 year mortality while being no more expensive than open surgery for colon cancer.     

Immunotherapy for De Novo renal transplantation: what's in the pipeline?

Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation.Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors.Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy.Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.     

Treatment strategies for acromegaly

Acromegaly is a chronic debilitating disorder caused by a growth hormone (GH)-producing pituitary adenoma. Active acromegaly is associated with a two- to fourfold increased mortality risk, mainly from cardiovascular disease. Transsphenoidal surgery is considered as the treatment of choice because of the rapidity of cure and normalisation of survival. Secondary treatment modalities are radiotherapy and medical treatment, and are important because surgery in the best hands cures only ~ 60% in long-term studies. Medical treatment with slow-release formulations of somatostatin are now widely used, also as primary treatment, and appear to be safe and effective in 50 – 60% of the patients. However, no data on mortality risk with these drugs is available. Recently, a GH-receptor blocking agent, pegvisomant, was licensed for use in acromegaly and appears to normalise IGF-1 in almost all patients. This article examines the pathophysiology of acromegaly, currently used medicines and their safety and efficacy, and the new drugs that are in development.