The British Society for Rheumatology Biologics Registers in Ankylosing Spondylitis (BSRBR-AS) study: Protocol for a prospective cohort study of the long-term safety and quality of life outcomes of biologic treatment.

BACKGROUND: Axial spondyloarthropathy typically has its onset in early adulthood and can impact significantly on quality of life. In the UK, biologic anti-tumour necrosis factor therapy is recommended for patients who are unresponsive to non-steroidal anti-inflammatory drugs. There remain several unresolved issues about the long-term safety and quality of life outcomes of biologic treatment in axial spondyloarthropathy. Long-term "real-world" surveillance data are required to complement data from randomised controlled trials. METHODS/DESIGN: We are conducting a UK-wide prospective cohort study of patients with axial spondyloarthropathy who are naïve to biologic therapy at the time of recruitment. Those about to commence anti-tumour necrosis factor biologic therapy will enter a "biologic" sub-cohort with other patients assigned to a "non-biologic" sub-cohort. The primary objective is to determine whether the use of biologic therapy is associated with an increased risk of serious infection, while secondary objectives are to assess differences in malignancy, serious comorbidity, all-cause mortality but also assess impact on specific clinical domains (physical health, mental health and quality of life) including work outcomes between biologic and non-biologic patient cohorts. Patients will be followed-up for up to 5 years. Data are obtained at baseline and at standard clinical follow-up visits - at 3, 6 and 12 months and then annually for the biologic cohort and annually for the non-biologic cohort. This study will also collect biological samples for genetic analysis. DISCUSSION: Although biologic therapy is widely used for ankylosing spondylitis patients who are unresponsive to non-steroidal anti-inflammatory drugs, the majority of the available safety information comes from rheumatoid arthritis, where increased infection risk has consistently been shown. However, given the typical demographic differences between rheumatoid arthritis and axial spondyloarthropathy patients, it is important to develop an epidemiologically rigorous cohort of patients receiving biologic therapy to effectively evaluate outcomes with regard not only to safety but also to quantify benefits across clinical, psychosocial and work outcomes. CLINICAL TRIAL REGISTRATION: This is an observational cohort study and clinical trial registration was not required or obtained.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide.

AIMS: A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS: Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS: In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS: Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

A novel breath-actuated integrated vortex spacer device increases relative lung bioavailability of fluticasone/salmeterol in combination.

BACKGROUND: Spacer devices facilitate respirable drug delivery. A novel breath-actuated antistatic spacer with integrated vortex chamber (Synchro-Breathe) device has been developed, which is compact,portable and user friendly as compared to conventional spacers which are bulky and cumbersome. The relative bioavailability to the lung of inhaled fluticasone and salmeterol combination is primarily dependent on respirable dose delivery and can be reliably quantified using adrenal suppression and early fall in serum potassium (marker of systemic beta-2 adrenoreceptor response) as surrogate markers for delivered lung dose. AIMS AND OBJECTIVES: To compare the in vivo relative bioavailability to the lung of Hydrofluoroalkane(HFA) Seretide delivered via Synchro-Breathe (SB); an optimally prepared 750 ml large volume plastic spacer, Volumatic (VM); and conventional Evohaler pMDI (EH). METHODS: Nineteen healthy volunteers completed the study using a randomised double blind, double dummy crossover design. Single doses of placebo or Seretide HFA 250 (total dose ex-valve: fluticasone 2000 mcg/salmeterol 200 mcg) were administered via SB, VM and EH. Overnight urinary cortisol creatinine (OUCC) and serum potassium (K) were measured at baseline and after each dose as systemic surrogates of relative respirable dose delivery for the fluticasone and salmeterol moieties, respectively. RESULTS: Significant suppression of OUCC and K occurred from baseline with SB and VM but not EH devices(geometric mean fold suppression, 95% CI, p and arithmetic mean fall mmol/L, 95% CI, respectively); EH:1.51(0.43-1.01), p 1/4 0.06; VM: 2.52(1.57-4.04), p < 0.001; SB: 2.66(1.57-4.49), p < 0.001(equating to 33.8%,60.2% and 62.3% falls, respectively). For K, the falls for EH were 0.09(0.25 to 0.07), p 1/4 0.69; VM: 0.27(0.46 to 0.08), p 1/4 0.003; SB: 0.32(0.53 to 0.11), p 1/4 0.002 (equating to 2.2%, 6.8%, and 8.06% fall,respectively). There were no significant differences between SB and VM. CONCLUSION: The breath-actuated Synchro-Breathe device was comparable to an optimally prepared Volumatic spacer, and resulted in commensurate improvement in relative lung bioavailability for both fluticasone and salmeterol moieties compared to pMDI.

Effect of aspirin on airway inflammation and pulmonary function in patients with persistent asthma.

BACKGROUND: Aspirin can cause bronchoconstriction in some asthmatic patients through increased production of proinflammatory mediators, particularly leukotrienes. However, recent in vivo evidence has suggested that aspirin also triggers the production of lipoxins, which act as natural antagonists of prostaglandins and leukotrienes. Aside from patients with known aspirin-sensitive asthma, physicians have avoided the use of aspirin in asthmatic patients in general because it was believed that this agent might precipitate worsening of their condition. OBJECTIVE: We sought to establish the effect of aspirin on pulmonary inflammation and function in patients with persistent asthma. METHODS: After withdrawal of their usual anti-inflammatory medication, patients with mild-to-moderate persistent asthma undertook double-blind, randomized, crossover treatment with 75 mg/d aspirin and placebo for 3 weeks each. Treatment evaluation included histamine challenge, spirometry, impulse oscillometry, total and alveolar exhaled nitric oxide measurement, and serum thromboxane B2 and 15-epilipoxin A4 levels. RESULTS: Fifteen patients completed the trial. Compared with placebo, there were no differences in histamine PC(20) values (0.17 doubling-dilution shift; 95% CI, -0.38 to 0.73; P = 1), exhaled nitric oxide levels (0.95-fold change; 95% CI, 0.45-2.00; P = 1), or any other inflammatory, spirometric, or oscillometry measurements. Aspirin led to a significant decrease in thromboxane B2 levels (17.53-fold difference; 95% CI, 5.46-56.49; P < .001). Baseline 15-epilipoxin A4 levels were increased at 4.88 ng/mL, and there was no increase with aspirin versus placebo (0.99-fold difference; 95% CI, 0.79-1.24; P = 1). CONCLUSION: In this preliminary study of 15 patients, low-dose aspirin did not lead to increased 15-epilipoxin A4 synthesis or alter inflammatory markers in patients with mild-to-moderate persistent asthma.

Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma.

BACKGROUND: Statins lower cholesterol and also exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. OBJECTIVE: To evaluate the in vivo therapeutic potential of simvastatin as an anti-inflammatory agent in patients with asthma. METHODS: Potential signal from treatment effect was optimized by withdrawing all anti-inflammatory treatment for the duration of the study. Participants received 1 month of daily simvastatin and 1 month of daily placebo in a randomized, double-blind crossover trial. A total of 16 patients completed per protocol. Asthmatic inflammation was evaluated by measuring exhaled tidal nitric oxide, alveolar nitric oxide, sputum and peripheral eosinophil count, methacholine hyperresponsiveness, salivary eosinophilic cationic protein, and C-reactive protein. Measurements of dynamic and static lung volumes and of cholesterol were also made. RESULTS: After initial withdrawal of usual asthma medication, there was a 1.43 geometric mean fold increase (ie, 43% difference) in fraction of exhaled nitric oxide (95% CI, 1.15 to 1.78; P = .004). Compared with placebo, simvastatin led to a 0.86 geometric mean fold decrease (95% CI, 0.7 to 1.04; P = .15) in exhaled nitric oxide (ie, a 14% difference), and a -0.18 doubling dilution shift (95% CI, -1.90 to 1.55; P = 1.0) in methacholine hyperresponsiveness. There were no significant differences in other inflammatory outcomes, lung volumes, or airway resistance between simvastatin and placebo. Treatment with simvastatin led to a significant reduction (P < .005) of total and low-density lipoprotein cholesterol. CONCLUSION: There is no evidence to suggest simvastatin has anti-inflammatory activity in patients with asthma. CLINICAL IMPLICATIONS: Simvastatin is not useful for the treatment of asthma.