Background: Proinflammatory cytokines, especially tumour necrosis factor a (TNF-a), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-a synthesis, may represent a novel and rational approach to the treatment of cancer cachexia. Aims: To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer. Methods: Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status. Results: Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm 3 in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference 22.59 kg (95% confidence interval (CI) 24.3 to 20.8); p = 0.005) and 4.46 cm 3 (absolute difference 25.6 cm 3 (95% CI 28.9 to 22.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm 3 in AMA compared with a loss of 3.62 kg (absolute difference 23.57 kg (95% CI 26.8 to 20.3); p = 0.034) and 8.4 cm

Cancer cachexia is a severe debilitating disorder for which there are currently few therapeutic options. It is driven by the release of pro-inflammatory cytokines and cachectic factors by both host and tumour. Over the past few years, basic science advances have begun to reveal the breadth and complexity of the immunological mechanisms involved, and in the process have uncovered some novel potential therapeutic targets. The effectiveness of thalidomide and eicosapentaenoic acid at attenuating weight loss in clinical trials also provides a further rationale for modulating the immune response. We are now entering an exciting period in cachexia research, and it is likely that the next few years will see effective new biological therapies reach clinical practice.

Early clinical features of lead toxicity are non‐specific and an occupational history is particularly valuable. Lead in the body comprises 2% in the blood (t1/2 35 days) and 95% in bone and dentine (t1/2 20–30 years). Blood lead may remain elevated for years after cessation from long exposure, due to redistribution from bone. Blood lead concentration is the most widely used marker for inorganic lead exposure. Zinc protoporphyrin (ZPP) concentration in blood usefully reflects lead exposure over the prior 3 months. Symptomatic patients with blood lead concentration >2.4 µmol l−1 (50 µg dl−1) or in any event >3.8 µmol l−1 (80 µg dl−1) should receive sodium calciumedetate i.v., followed by succimer by mouth for 19 days. Asymptomatic patients with blood lead concentration >2.4 µmol l−1 (50 µg dl−1) may be treated with succimer alone. Sodium calciumedetate should be given with dimercaprol to treat lead encephalopathy.

Forty years on from its worldwide withdrawal, thalidomide is currently undergoing a remarkable renaissance as a novel and powerful immunomodulatory agent. Over the last decade it has been found to be active in a wide variety of inflammatory and malignant disorders where conventional therapies have failed. Recently, considerable progress has been made in elucidating its complex mechanisms of action, which include both anticytokine and antiangiogenic properties. However, in addition to its well known teratogenic potential, it has a significant side effect profile that leads to cessation of treatment in up to 30% of subjects. In response to this, two new classes of potentially safer and non-teratogenic derivatives have recently been developed. This review summarises the biological effects, therapeutic applications, safety profile, and future potential of thalidomide and its derivatives.

IntroductionBiosimilar infliximab (CT-P13) has been licensed for the treatment of IBD in Europe for over a year with the potential for significant cost savings. However, uptake in the UK has been slow primarily due to concerns over the lack of safety and efficacy data particularly with regard to switching patients from the originator product. We present the preliminary data from a controlled switch programme in a cohort of adult IBD patients.MethodsA prospective study was undertaken to assess the safety and efficacy of switching patients receiving originator infliximab (Remicade) to its biosimilar (CT-P13). Patient demographic data was collected along with disease severity scores (HBI and SCCAI), biological markers of disease activity, drug and antibody levels and PROM data (IBD-Control questionnaire) prior to the switch and at each subsequent infusion visit. Evaluation of the efficacy of biosimilar infliximab at the time of the last infusion was compared with the originator at switch over. Means, medians, and ranges were calculated. Adverse events were prospectively collected.Results78 IBD patients were included in the cohort (63 CD and 15 UC). The average age for the CD and UC patients was 43 and 42 years respectively. The average length of therapy on Remicade prior to the switch was 46 months for CD and 25 months for UC. 66/78 (85%) patients were receiving the standard dosage of 5 mg/kg 8 weekly with 12/78 (15%) either on a shortened interval or a 10 mg/kg dose. 42/63 (67%) of CD patients were in remission at switch over compared to 43/60 (72%) at the most recent infusion (4–6 months). The number of patients with mild, moderate and severe disease remained stable throughout the study period (Mild 10/63 (16%) v 11/60 (18%): Moderate 10/63 (16%) v 5/60 (8%): Severe 1/63 (2%) v 1/60 (2%)). 9/15 (60%) of UC patients were in remission at switch over compared with 11/13 (85%) at the most recent infusion. There was no difference in the mean CRP before and after the switch in either CD patients (5.4 vs 5.6 p=0.32) or UC patients (3.1 vs 3.0 p=0.73). The mean patient questionnaire score data also remained unchanged before and after the switch (CD 4.4 vs 4.0 p=0.56, UC 4.9 vs 3.1 p=0.61). Five patients (3 CD, 2 UC) discontinued infliximab during the study period (3 switched biological class, 1 infusion reaction, 1 deep remission). There were no adverse safety signals with one infusion reaction (1/283 infusions) and the rate of mild adverse events unchanged from before and after the switch.ConclusionSwitching patients with IBD from originator infliximab to biosimilar infliximab appears both safe and effective. Wider uptake in the UK would result in considerable cost savings to the NHS.Disclosure of InterestNone Declared

IntroductionBiosimilar infliximab (CT-P5013) has been licensed in the UK for over a year with the potential for significant cost savings, though uptake to-date has been surprisingly slow. We report the introduction of biosimilar infliximab through a closely managed switching programme.MethodsFollowing the licensing of biosimilar infliximab we made a decision to instigate a closely managed switching programme encompassing all patients on maintenance treatment with Remicade and all new starters. A working party was set up with strong managerial support to deliver the project. We initially estimated savings of £400,000/year to the local health economy. Following meetings with the 3 local CCGs agreement was confirmed for a 50:50 gain share agreement between the CCGs and the Trust. To facilitate and monitor the switching programme a new Band 7 IBD Biological nurse, a Band 7 IBD Biological pharmacist, and an IBD administrator were recruited. All patients were informed by letter of the planned switch and the rationale for it. A variety of clinical and biological markers were also recorded at each visit along with PROM data.ResultsTo date since the start of the project on 16th September 2015 88 patients have been treated with biosimilar infliximab. 78 (63 CD/15 UC) patients on maintenance treatment with Remicade were switched to CT-P13 with unchanged efficacy and safety (the detailed results are the basis of a separate abstract); a further 10 patients received induction therapy (7 CD/3 UC). 3/88 patients requested further clarification from the IBD team with all patients subsequently agreeing to the switch. All patients were seen by either the IBD pharmacist or IBD specialist nurse and stated they felt well informed. Over the first six months the programme has generated total cost savings of £232,576.52 with projected year savings of £540,000. Staff costs totalled £90,000. PROM data from the cohort revealed very high satisfaction with treatment with a mean score of 7.3 (Range 3–10) for overall disease control. Patient feedback was universally positive.ConclusionThe introduction of biosimilar infliximab can be achieved through a closely managed programme with very significant cost savings to the local health economy. Engaged conversations between primary and secondary care facilitate realising these savings allowing investment in the local IBD service with direct impact on patient care. Patients were overwhelmingly supportive of the project. Wider uptake in the UK would result in considerable cost savings to the NHS.Disclosure of InterestNone Declared

No abstract

The discovery of the central role of tumour necrosis factor-α in Crohn's disease and the subsequent introduction of infliximab into routine clinical practice has transformed the treatment of refractory disease. Advances in understanding of the immunopathological basis of Crohn's disease are leading to the development of new biological therapies which are likely to play an increasing role in future.