Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study.

BACKGROUND: Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, which is currently under investigation for treatment of moderate-to-severe plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL-17 inhibitors for psoriasis. OBJECTIVES: To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies. METHODS: Forty-nine patients with moderate-to-severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28. RESULTS: At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated with nonlesional skin. CONCLUSIONS: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.

Additive bronchoprotective and bronchodilator effects with single doses of salmeterol and montelukast in asthmatic patients receiving inhaled corticosteroids.

OBJECTIVE: We wished to evaluate whether the combination of a leukotriene receptor antagonist and long-acting beta(2)-agonist might confer additive beneficial effects in terms of bronchoprotection and bronchodilatation, in mild to moderate asthmatic patients who were suboptimally controlled on inhaled corticosteroids alone. METHODS: Twelve asthmatic patients were enrolled into a single-blind, placebo-controlled, crossover study, receiving additive therapy as either of the following: (1) montelukast alone, 10 mg (ML(10)); (2) inhaled salmeterol alone, 50 microg (SM(50)); (3) ML(10) and SM(50); (4) ML(10) and inhaled salmeterol, 100 microg (SM(100)); or (5) placebo inhaler and tablet. Trough measurements were made of adenosine monophosphate (AMP) bronchial challenge (the provocative concentration of a drug [AMP] causing a fall of >/= 20% in FEV(1) [PC(20)]) as the primary end point, and spirometry, following single doses of either placebo or active treatments (12 h after salmeterol, and 24 h after monteleukast, respectively). RESULTS: Compared to placebo, all active treatments led to significant improvements (p < 0.05) in geometric mean AMP-PC(20): placebo, 42 mg/mL; ML(10), 106 mg/mL; SM(50), 115 mg/mL; ML(10) and SM(50), 183 mg/mL; and ML(10) and SM(100), 247 mg/mL. The effects of montelukast and salmeterol were numerically additive, with ML(10) and SM(100) being significantly different (p < 0.05) from ML(10) alone. For mean FEV(1) and forced expiratory flow rate between 25% and 75% of vital capacity, there were significant differences (p < 0.05) between both combination therapies vs ML(10) alone. CONCLUSIONS: Our results suggest additive benefits of a single dose of a long-acting beta(2)-agonist and leukotriene antagonist, in terms of bronchoprotection and bronchodilation. Further studies in more severe asthmatics are required to evaluate long-term clinical effects.

Netilmycin and vancomycin in the treatment of peritonitis in CAPD patients.

This study was undertaken to evaluate: 1. The efficacy of netilmycin and vancomycin as combined first line antimicrobial regime, compared to cefuroxime, in the treatment of peritonitis. 2. To measure the levels of netilmycin and vancomycin in the serum and dialysate. 3. To report on the use of this combination over a one year period and compare it with that of cefuroxime used during the previous one year.

The use of glucose polymer (icodextrin) in peritoneal dialysis: an overview.

The osmotic effectiveness of glucose polymer is now well established. The relative inertness of this macromolecular compound has been the key factor in its success as the first "colloid" osmotic agent in clinical use. In its present form it sustains ultrafiltration for up to 12 hours, and a daily overnight use would obviate the need for hypertonic exchanges, especially 3.86% glucose. In addition, it could be used in automated peritoneal dialysis regimens to enhance ultrafiltration and solute clearance during the daytime. Preliminary reports also indicate that it is beneficial in diabetic patients and in some patients who have lost ultrafiltration. Although systemic accumulation of glucose polymer breakdown products occurs, it reaches steady-state levels quickly (within 2 weeks) and remains stable throughout the duration of polymer use. In the long-term study these levels of maltose and oligosaccharides over 2.5 years represent the longest exposure of these substances in uremic patients without any clinical or metabolic adverse effects and provides important evidence of its safety. Future work based on ongoing studies suggests that a family of physiological solutions ("bimodal" preparations in iso-osmolar combination) could be available, and the individual's dialysis prescription could be tailored to take into account the ultrafiltration and metabolic needs. Icodextrin will be a key component of such solutions.

Optimal use of glucose polymer (icodextrin) in peritoneal dialysis.

The osmotic effectiveness of glucose polymer is now well established. The relative inertness of this macromolecular compound has been the key factor in its success as the first "colloid" osmotic agent in clinical use. In its present form, it produces sustained ultrafiltration for up to 12 hours, and a daily overnight use would obviate the need for hypertonic exchanges, especially 3.86% glucose. In addition, it could be used in automated peritoneal dialysis regimes to enhance ultrafiltration and solute clearance during the daytime. Preliminary reports also indicate that it is beneficial in diabetic patients and in some patients who have lost ultrafiltration. The new "bimodal" formulations look promising, with the potential to replace all the currently used hyperosmolar exchanges with physiological solutions. Although systemic accumulation of glucose polymer breakdown products occurs, it reaches steady-state levels quickly (within two weeks) and remains stable throughout the duration of polymer use. In the long-term study, these levels of maltose and oligosaccharides over three-and-a-half years represent the longest exposure of these substances in uremic patients without any clinical or metabolic adverse effects and provide an important evidence of safety. Future work based on studies that are ongoing suggest that a family of physiological solutions ("bimodal" preparations in iso-osmolar combination) could be available, and the individual's dialysis prescription could be tailored to take into account the ultrafiltration, metabolic needs, as well as the long-term viability of the membrane. Glucose polymer will be a key component of such solutions.

Peritonitis occurrence in a multicenter study of icodextrin and glucose in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Dialysis.

OBJECTIVE: To compare peritonitis occurrence and outcome in a large U.K. study Multicentre Investigation of Icodextrin in Ambulatory Dialysis (MIDAS). DESIGN: Prospective, randomized, controlled 6-month comparison of icodextrin with glucose for the long dwell in continuous ambulatory peritoneal dialysis (CAPD) patients. SETTING: Eleven CAPD units in U.K. teaching hospital. PATIENTS: A total of 209 patients established on CAPD for at least 3 months (103 control, 106 icodextrin). Twenty-three control (C) and 22 icodextrin (I) patients experienced peritonitis during the study. INTERVENTION: Patients who had peritonitis remained on treatment (unless CAPD was withdrawn, temporarily or permanently). MAIN OUTCOME MEASURES: The main outcome measures were the rate of peritonitis and duration of CAPD treatment prestudy; the rate of peritonitis episodes and their outcome during study; the effect of peritonitis on laboratory variables, serum icodextrin metabolites, and ultrafiltration efficacy. RESULTS: Prestudy: Nine (39%) of C but 14 (64%) of I patients had suffered previous peritonitis episode(s), with overall rates of 0.58 and 0.78 episodes per patient-year, respectively. DURING STUDY: There were 31 C episodes and 35 I episodes, with overall rates of 0.76 and 0.93 per patient-year, respectively. The increase in the C and I groups was 31% and 19%, respectively. Serum osmolality and sodium levels were unaffected by peritonitis, and there was no increase in serum icodextrin metabolites during peritonitis. Overnight ultrafiltration volume during peritonitis (mean +/- SD) declined slightly from 218 +/- 354 mL to 185 +/- 299 mL (NS) in the control group, but increased in the icodextrin group from 570 +/- 146 mL to 723 +/- 218 mL (p < 0.01). CONCLUSIONS: Using icodextrin for the long dwell in CAPD does not increase the rate of peritonitis, nor does it alter the outcome of peritonitis. Peritonitis does not affect uptake of icodextrin from the peritoneum.

Cell function and viability in glucose polymer peritoneal dialysis fluids.

OBJECTIVE: To investigate the biocompatibility profile of a new peritoneal dialysis fluid containing glucose polymer (GPF). DESIGN: Viability and function of peripheral neutrophils (PMN) from healthy donors and cultured human peritoneal mesothelial cells were assessed in vitro after exposure to dialysis fluids. Phagocytosis, leukotriene B4 synthesis, and respiratory burst activation were measured following stimulation with serum-treated zymosan (STZ) or opsonized Staphylococcus epidermidis (S. epidermidis). Bacterial growth in the fluids was also investigated. In vivo pH equilibration of GPF and subsequent respiratory burst activation following incubation in spent dialysate were studied. RESULTS: For all the host defense parameters measured, commercial dialysis fluids (Dianeal; 1.36% and 3.86% glucose) and GPF (pH 5.2) were significantly more inhibitory than the control buffer (pH 7.3). Mesothelial cell viability was reduced by all the fluids tested irrespective of pH. Glucose polymer fluid was significantly more inhibitory than Dianeal 1.36% for STZ phagocytosis and respiratory burst activation. In contrast, it was less suppressive than Dianeal 3.86% for LTB4 synthesis. For all parameters tested, except LTB4 generation, there was a marked effect of pH, with GPF being significantly more inhibitory at pH 5.2 than at pH 7.3. None of the fluids tested supported the growth of S. epidermidis, although the viable counts in GFP were significantly higher than in Dianeal. Fluid inhibition of PMN respiratory burst activation and cytotoxicity were reduced in a time-dependent manner following increasing dwell time in vivo. CONCLUSIONS: GPF does not appear to be significantly different from Dianeal as far as host defense parameters are concerned. However, the cell viability and bacterial survival data suggest some possibly negative aspects of this fluid formation.

Recovery from sensorineural deafness in Wegener's granulomatosis.

Wegener's granulomatosis may present with deafness or other aural symptoms. This report describes two patients with histological evidence of Wegener's granulomatosis who developed reversible sensorineural hearing loss during the course of their illness. The first patient showed complete recovery of a sensorineural hearing loss averaging 50 dB after ten months treatment with cyclophosphamide and high-dose prednisolone. The second patient, who was on maintenance haemodialysis, achieved a 40 dB improvement in sensorineural hearing loss within two weeks of adding cyclophosphamide to pre-existing corticosteroid therapy. These findings suggest that the prognosis of sensorineural hearing loss in Wegener's granulomatosis can be improved with suppression of the vasculitic process by early treatment with combined cytotoxic-immunosuppressive therapy.

Incidence of advanced chronic renal failure and the need for end stage renal replacement treatment.

OBJECTIVE: To determine the age related incidence of advanced chronic renal failure in two areas of England. DESIGN: Prospective study of patients newly identified as having advanced chronic renal failure within a two year period; subsequent monitoring of patients' clinical course for a further 26 months. SETTING: Devon and Blackburn. SUBJECTS: Those patients in a population of 708,997 who developed advanced chronic renal failure (serum creatinine concentration greater than 500 mumol/l) for the first time during a two year period. MAIN OUTCOME MEASURES AND RESULTS: 210 Patients (148 per million population per year) developed advanced chronic renal failure, 117 (51%) of whom were over 70. The age related incidence rose from 58 per million per year in those aged 20-49 to 588 per million per year in those aged 80 or over. Only 54% (113) of patients were referred to a nephrologist; 120 patients (57%) needed dialysis or died within three months of presenting without receiving dialysis, and 187 (89%) died or needed dialysis within three years. After those unsuitable for further treatment had been excluded, 78 patients per million population per year aged under 80 needed to start long term renal replacement treatment. CONCLUSIONS: Many patients suitable for renal replacement treatment are still not referred for nephrological opinion and are denied treatment. If the treatment rate in the United Kingdom rose from the 1988 rate of 55.1 per million per year to 78 per million per year then the number of patients receiving treatment would rise to about 800 per million. This is double the present number and has considerable but predictable resource implications for the NHS.

How sweet is the pacemaker?

Pacemaker infections can be difficult to diagnose, especially when they present with non-specific symptoms and signs a long time after insertion of the device. Unidentified or partially treated low-grade chronic sepsis can result in multisystem disease processes with significant mortality and morbidity. Therefore, a high index of suspicion is required to identify the pacemaker as the source of sepsis and treat it effectively. This report describes a case of chronic pacemaker wire infection, which eventually presented with Sweet's syndrome, a rare manifestation of infective endocarditis.