Nocebo Effect Is Difficult to Diagnose in Patients Switched to Biosimilars

The nocebo effect, defined as a worsening of symptoms or the onset of new clinical issues as a result of a patient’s negative attitude toward a chosen regimen, may account for some treatment failures in transitions from originator biologics to respective biosimilars, but nocebo is a challenging diagnosis, according to a recent study.

Investigators sought to understand the nocebo effect in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Nocebo can be difficult to diagnose due to the absence of diagnostic criteria, different pathological backgrounds for inflammatory rheumatic disorders versus other disorders investigated, and the absence of specific neurochemical and neuroimaging studies, according to Cantini et al.

“To the best of our knowledge, with the exclusion of fibromyalgia, no studies investigating the pathophysiology of nocebo in patients with inflammatory rheumatic disorders have been published,” authors of the study wrote.

Multiple biosimilars of reference biologics, including etanercept, infliximab, adalimumab, and rituximab, are available worldwide for the treatment of inflammatory rheumatic diseases. Outside of the United States, governments have recommended or imposed the use of biosimilars bearing in mind therapeutic equivalence with reference products and potential cost savings.

Gaps in patients’ and providers’ knowledge and perception of biosimilars can be a hindrance for future biosimilar uptake and may contribute to the nocebo effect, thereby reducing the clinical benefit. Often during studies, discontinuations are attributed to the nocebo effect after all other potential causes have been ruled out. The many challenges of understanding nocebo, compounded by the many variables across disease types and lack of complete investigation, mean that the discretion of individual clinicians remains paramount in determinations of nocebo, the authors wrote.

In their review of therapy discontinuations after patients switched from originators to biosimilars in select clinical trials of RA, PsA and SpA, investigators found that the nocebo effect accounted for up to 83.6% of withdrawals from biosimilar regimens.

In a review of randomized clinical trials and their open-label extension phase, including studies of transitions from reference drugs to biosimilars (including infliximab, etanercept, and rituximab), the discontinuation rates ranged from 5% to 33.3%. Discontinuation was high for open-label trials versus RCTs (median 14.3% versus 6.95%, respectively). Patients’ negative expectations were chiefly responsible for treatment failures, because discontinuations were mostly not attributable to adverse events, investigators said.

The most frequent clinical manifestations of nocebo include pain exacerbation, drowsiness, nausea, headache, insomnia, migraine, or motor performance deterioration, according to investigators. Symptoms vary across disease types, however.

None of the studies investigated the neurochemical pathways and the neuroimaging features attributed to nocebo, investigators noted.

”The variability of clinical features, the nonspecificity of symptoms, and the different conditions where the [nocebo effect] was investigated did not allow formulation of classification/diagnostic criteria and appropriate outcomes measures useful to address the real burden of nocebo accurately, they wrote.”

Nocebo has been investigated extensively in anesthesiology and neurology, investigators wrote. The rate of nocebo in neurology trials ranged from 18.5% to 78.3% in patients with different brain disorders.

Reviews of randomized controlled trials of fibromyalgia, a condition believed to amplify painful sensations, demonstrated that nocebo was responsible for 67.2% to 81.7% of adverse events in the active drug arms. Investigators said 9.5% of therapy discontinuations were attributed to worsening of disease without clinical reasons. However, frequent fibromyalgia-associated depression and different assessment strategies limited the association with the nocebo effect.

Neuroimaging studies have helped to confirm that different neurotransmitter pathways are involved in nocebo versus placebo effects. Magnetic resonance imaging and positron emission tomography showed distinct nocebo-activated brain areas, such as anterior insula, prefrontal cortex, and hippocampus. Investigators said gender, depression, pessimism, and physician’s verbal information also predisposed patients to nocebo.

Studies investigating the nocebo mechanisms in RA, PsA, and SpA are needed to determine whether the complicated immune-mediated pathogenesis of these disorders may imply different cerebral pathways than for patients with neurological diseases, the authors said.

Two studies assessed outcomes for patients who switched back to originator drugs. “No changes of disease activity were recorded in 5 patients with RA, while bath ankylosing spondylitis disease activity index, ankylosing spondylitis disease activity score, and global disease activity significantly improved in 33 patients with SpA,” the authors wrote. In the second study, no differences were noted in patients (n = 120) who switched from the biosimilar etanercept to reference etanercept. The retention rate was high among back-switchers (n = 104 [87%]).

Reference

Cantini F, Niccoli L, Franchi G, Damiani A, Benucci M. The nocebo effect in rheumatology: an unexplored issue. IMAJ. 2020;22(3):185-190.