Low-dose theophylline in addition to ICS therapy in COPD patients: A systematic review and meta-analysis

Abstract

Background A synergism has been reported between theophylline and corticosteroids, wherein theophylline increases and restores the anti-inflammatory effect of inhaled corticosteroids (ICS) by enhancing histone deacetylase-2 (HDAC) activity. Several studies have explored the efficacy of low-dose theophylline plus ICS therapy on chronic obstructive pulmonary disease (COPD) but the results are discrepant. Method We conducted searches in electronic database such as PubMed, Web Of Science, Cochrane Library, and Embase to find out original studies. Stata/SE 15.0 was used to perform all data analysis. Result A total of 47,556 participants from 7 studies were included in our analysis and the sample size of each study varied from 24 to 10,816. Theophylline as an add-on therapy to ICS was not associated with the reduction of COPD exacerbations (HR: 1.08, 95% CI: 0.97 to 1.19, I2 = 95.2%). Instead, the theophylline group demonstrated a higher hospitalization rate (HR: 1.12, 95% CI: 1.10 to 1.15, I2 = 20.4%) and mortality (HR: 1.19, 95% CI: 1.14 to 1.25, I2 = 0%). Further, the anti-inflammatory effect of low-dose theophylline as an adjunct to ICS on COPD was controversial. Besides, the theophylline group showed significant improvement in lung function compared with the non-theophylline group. Conclusion Based on current evidence, low-dose theophylline as add-on therapy to ICS did not reduce the exacerbation rate. Instead, the hospitalization rate and mortality increased with theophylline. Thus, we do not recommend adding low-dose theophylline to ICS therapy in COPD patients. Trial registration PROSPERO Registration CRD42021224952.

Blood Eosinophils in Chinese COPD Participants and Response to Treatment with Combination Low-Dose Theophylline and Prednisone: A Post-Hoc Analysis of the TASCS Trial

“…This has some precedent, as a recent meta-analysis of seven studies investigating the use of concomitant administration of theophylline with inhaled corticosteroids found that their coadministration may lead to an increased risk of COPD-related hospitalization and mortality in the patient population. 28 Relevant to this may also be evidence from studies such as TORCH, which demonstrated the risk of pneumonia through regular use of inhaled corticosteroids. A recent cohort study reported that rheumatoid arthritis participants prescribed low-dose systemic glucocorticosteroids were significantly more likely to be admitted to hospital for infection.…”

Pharmacological therapy for stable chronic obstructive pulmonary disease

“…The precise treatment efficacy of methylxanthine in COPD remains controversial. Multiple RCTs have revealed that aminophylline does not minimize the risk of acute COPD exacerbation or other primary clinical endpoints and may even increase the hospitalization rate and long‐term mortality 32 . In a randomized, three‐arm, double‐blind, placebo‐controlled study conducted at 37 centers in China, symptomatic patients with moderate‐to‐severe COPD were randomly assigned to one of three groups (placebo, low‐dose theophylline, and low‐dose theophylline and prednisone).…”

“…Multiple RCTs have revealed that aminophylline does not minimize the risk of acute COPD exacerbation or other primary clinical endpoints and may even increase the hospitalization rate and long‐term mortality. 32 In a randomized, three‐arm, double‐blind, placebo‐controlled study conducted at 37 centers in China, symptomatic patients with moderate‐to‐severe COPD were randomly assigned to one of three groups (placebo, low‐dose theophylline, and low‐dose theophylline and prednisone). Compared with the placebo, low doses of theophylline alone or combined with prednisone did not reduce the rate of acute COPD exacerbations.…”

Inhaled theophylline: old drug new tricks?

“…However, it was also observed that theophylline improved lung function compared to the non-theophylline group. 34…”