Abstract
Prospective, double-blind, randomized, placebo-controlled studies are considered to provide the highest quality of interventional evidence. This meta-analysis summarizes the frequencies of adverse events according to the Medical Dictionary for Regulatory Activities (MedDRA) in the placebo arms of 101 such studies in rheumatoid arthritis, including a total of 17,150 patients in the placebo arms and 37,819 patients in the verum arms. Placebo-treated patients reported more than one adverse event in a median of 55.0%, 65.5%, and 72.5% (compared to 72.3% in the verum arms), and a serious adverse event in 2.5%, 5.8%, and 8.6% (compared to 5.9% in the verum arms), with stable doses of corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs as background therapies, respectively. Odds ratios were comparable between placebo and verum arms for nausea (1.00 with 95% confidence interval (CI) 0.86–1.17), for hepatobiliary disorders (1.08 with CI 0.85–1.36), for abnormal hepatic functions (1.09 with CI 0.83–1.44), and general disorders and administration site conditions (1.39 with CI 0.95–2.03). A publication bias has to be assumed for nausea (p = 0.018; Egger’s test), diarrhoea (p = 0.022), and serious infections and infestations (p = 0.009). In conclusion, patients should be aware that “adverse events” may occur even with placebo medication, independent from an additional verum medication added to the background therapy. Further studies are warranted to respect and overcome the psychological and other issues related to these placebo-related “adverse events”.
Highlights
Rheumatoid arthritis (RA) affects about 0.5% of the population in the industrialized world [1]
Patients should be aware that “adverse events” may occur even with placebo medication, independent from an additional verum medication added to the background therapy
Studies were sub-grouped according to their mechanism of action, with dihydroorotate dehydrogenase (DHODH) inhibitor leflunomide and methotrexate as csDMARDs, januse kinase (JAK) inhibitors as tsDMARDs and blockers of antitumor necrosis factor-alpha, cytotoxic T lymphocyte-associated protein-4, the B-cell marker CD20 or the interleukin-6 receptor and the interleukin-1 receptor antagonist (IL1RA) as bDMARDs
Summary
Rheumatoid arthritis (RA) affects about 0.5% of the population in the industrialized world [1]. From the patients’ perspective, knowledge about the disease itself and available treatment options must be considered a prerequisite for shared decision-making [5] For this purpose, information on the pros and cons of the available options is usually derived from placebo-controlled, doubleblind, randomized trials, which provide high-level evidence for the conversation between patients and their clinicians. Placebos are regularly used as controls in prospective, double-blind trials, with randomization of participants before study entry into a verum and a placebo arm to eliminate any treatment-related bias These studies are considered the most reliable source of clinical evidence, they were used to analyze the frequency of adverse effects in placebo-treated patients. Besides the high frequency of such adverse events even in placebo-treated RA patients, the underlying reasons for a possible influence of the verum medication on adverse events in randomized studies deserve further investigation
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