Rationale

Bimagrumab is a fully human monoclonal antibody that blocks the activin type II receptors, preventing the activity of myostatin and other negative skeletal muscle regulators.

Objectives

To assess the effects of bimagrumab on skeletal muscle mass and function in patients with chronic obstructive pulmonary disease (COPD) and reduced skeletal muscle mass.

Methods

Sixty-seven patients with COPD (mean FEV₁, 1.05 L [41.6% predicted]; aged 40-80 yr; body mass index < 20 kg/m² or appendicular skeletal muscle mass index ≤ 7.25 [men] and ≤ 5.67 [women] kg/m²), received two doses of either bimagrumab 30 mg/kg intravenously (n = 33) or placebo (n = 34) (Weeks 0 and 8) over 24 weeks.

Measurements and main results

We assessed changes in thigh muscle volume (cubic centimeters) as the primary endpoint along with 6-minute-walk distance (meters), safety, and tolerability. Fifty-five (82.1%) patients completed the study. Thigh muscle volume increased by Week 4 and remained increased at Week 24 in bimagrumab-treated patients, whereas no changes were observed with placebo (Week 4: +5.9% [SD, 3.4%] vs. 0.0% [3.3%], P < 0.001; Week 8: +7.0% [3.7%] vs. -0.7% [2.8%], P < 0.001; Week 16: +7.8% [5.1%] vs. -0.9% [4.5%], P < 0.001; Week 24: +5.0% [4.9%] vs. -1.3% [4.3%], P < 0.001). Over 24 weeks, 6-minute-walk distance did not increase significantly in either group. Adverse events in the bimagrumab group included muscle-related symptoms, diarrhea, and acne, most of which were mild in severity.

Conclusions

Blocking the action of negative muscle regulators through the activin type II receptors with bimagrumab treatment safely increased skeletal muscle mass but did not improve functional capacity in patients with COPD and low muscle mass. Clinical trial registered with www.clinicaltrials.gov (NCT01669174).

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data.

Background

Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications.

Purpose

The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.

Methods

An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards.

Results

We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality.

Conclusions

Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.