Jonathan Burdon

Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

BACKGROUND The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. FUNDING CSL Behring.

α1-Antitrypsin deficiency and anti-proteinase 3 antibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis

α1‐antitrypsin (α1‐AT) is a naturally occurring inhibitor of proteinase 3 (PR3) and elastase, two of the target antigens of anti‐neutrophil cytoplasmic antibodies (ANCA). An increased incidence of α1‐AT phenotypes associated with dysfunctional α1‐AT or low serum levels has been reported in patients with anti‐PR3 antibodies. We have studied the relationship between ANCA, and phenotypes and serum levels of α1‐AT. Phenotypes usually associated with a moderate or severe reduction in α1‐AT serum levels or in dysfunctional activity were found more often in individuals with anti‐PR3 antibodies than in the general population: four of the 31 patients (13%) with anti‐PR3 antibodies had phenotypes MZ (n= 2), S (n= 1) or Z (n= 1) (P < 0·05). However, the corresponding α1‐AT serum levels were normal (n= 3) or elevated (n= 1). None of the 31 sera with anti‐PR3 antibodies had low levels of α1‐AT. No abnormal α1‐AT phenotype was demonstrated in seven patients with anti‐elastase antibodies, despite a low level of α1‐AT in one serum. Anti‐myeloperoxidase antibodies are common in patients with ANCA, but no abnormal phenotype or low serum oi‐AT level was demonstrated in any of 29 sera containing these antibodies. Finally anti‐glomerular basement membrane (GBM) antibodies occur occasionally in patients with ANCA‐associated diseases, but again none of 10 sera had an abnormal α1‐AT phenotype or low serum level. ANCA were not demonstrated by indirect immunofluorescence in any serum from 73 patients with abnormal α1‐AT phenotypes. These results confirm that patients with anti‐PR3 antibodies often have α1‐AT phenotypes that are usually associated with low serum levels of α1‐AT or with dysfunctional protein. Nevertheless, the incidence of anti‐PR3 antibodies in patients with abnormal α1‐AT phenotypes is very low. This probably reflects the rarity of Wegeners granulomatosis, the major disease associated with anti‐PR3 antibodies, and the relative frequency of abnormal α1‐AT phenotypes. The mechanism for the development of anti‐PR3 antibodies in patients with abnormal α1‐AT phenotypes is not clear, but may relate to the increased propensity of unbound and uninhibited PR3 to stimulate autoantibody production.

Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor

Palovarotene is an oral &ggr;-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the &agr;1-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day−1 palovarotene given for 1 year to 262 patients with severe &agr;1-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day−1 over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe &agr;1-antitrypsin deficiency.

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE).

BACKGROUND Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. METHODS Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. FINDINGS Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. INTERPRETATION RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. FUNDING CSL Behring.

The proteinase–antiproteinase theory of emphysema: A speculative analysis of recent advances into the pathogenesis of emphysema

Abstract This review concerns the reasons why only an estimated 10–15% of patients with alpha‐1‐antitrypsin (A1AT) deficiency develop the destructive lung disease known as emphysema. The arguments presented revolve around the proteinase‐antiproteinase balance in the ‘micro‐environment’ of the epithelial space of the lung. Attention is focused on the balance between destructive enzymes such as neutrophil elastase and protective proteins such as A1AT, secretory leucocyte proteinase inhibitor (SLPI), human elastase inhibitor (HEI) and elafin. When neutrophil elastase is already attached to the elastin fibres the smaller molecules SLPI and elafin appear to be better inhibitors of this enzyme than larger inhibitors such as A1AT and HEI. Furthermore, SLPI and elafin may provide the first line of defence against proteinase attack from neutrophil elastase. In trying to explain the variability in the clinical expression of A1AT‐deficiency and the development of emphysema, the importance of changes to A1AT, SLPI and elafin molecules induced by smoking and/or oxygen free radicals has been considered. It is possible that emphysema only develops in patients who have SLPI/elafin deficiency as well as A1AT deficiency.

Mitochondrial myoneuropathy with respiratory failure and myoclonic epilepsy: A case report with biochemical studies

A 55-year-old man is presented who developed severe multifocal myoclonus and tonic clonic seizures in his early thirties, and progressive limb weakness in his mid forties, when a ragged red fibre myopathy was diagnosed. He went on to develop a distal motor neuropathy and respiratory failure. Respiratory function tests indicated respiratory failure secondary to respiratory muscle weakness and a central hypoventilation syndrome. CT scan revealed brain stem atrophy and brain stem evoked responses were abnormal. A sural nerve biopsy showed severe axonal degeneration. Cytochrome difference spectra and polarographic studies on isolated intact muscle mitochondria were normal. This study reports the association of respiratory failure and sleep apnoea with Fukuharas syndrome and presents biochemical data suggesting that the mitochondrial respiratory chain may be intact in some patients with this syndrome.

Respiratory function tests and their application

This document attempts to provide a broad consensus statement about common practice in respiratory function testing and the use of its results in assessing respiratory disease and disability. It is written for respiratory and general clinicians. General principles only are provided and the source documents are referenced but detail is not exhaustive and technically the document does not attempt to provide best practice guidelines. It is meant to reflect usual practice and in some individual patients use of respiratory function tests outside these guidelines may clearly be appropriate in particular clinical circumstances. General statements about quality assurance and cost benefit will be given at the end of the document but for each individual test there are sections on description, indications, interpretation, normal values, specific quality assurance and cost benefit. The scope of the document will cover tests of mechanical function, gas exchange and exercise assessment.

Secretory leukocyte proteinase inhibitor, alpha-1-antitrypsin deficiency and emphysema: Preliminary study, speculation and an hypothesis

Objectives:  This study investigated (i) whether adequate concentrations of secretory leukocyte proteinase inhibitor (SLPI) in the lungs of alpha‐1‐antitrypsin (A1AT) deficient patients can explain the variability in the development of emphysema in these individuals, and (ii) whether cigarette smoking jeopardises the protective screen provided by functional SLPI.

Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients

BACKGROUND & AIMS Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. METHODS Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations. RESULTS A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. CONCLUSION PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. LAY SUMMARY Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency. CLINICAL TRIAL REGISTRATION NUMBER NCT02363946.

Decline in FEV1 in patients with PiZ alpha-1-antitrypsin deficiency: the Australian experience.

Objective: Alpha‐1‐antitrypsin (α1antitrypsin) deficiency is a rare hereditary disorder which characteristically presents with emphysema at an early age. The aim of the present study was to determine whether the rate of decline of lung function in α1antitrypsin‐deficient subjects in Australia was similar to that found elsewhere.