AB1350 HOW TO REDUCE THE NOCEBO EFFECT IN RHEUMATOLOGY? A SYSTEMATIC REVIEW OF RISK FACTORSAND INTERVENTION STRATEGIES
Authors: Juliette Petit, Karine Louati, Francis Berenbaum, Catherine Beauvais
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Nocebo effect (NE) defines any declared negative side effect of a drug that is non-specific, non-explained by its pharmacokinetic, and non-dose dependant. Recently, it has been pointed out as the main factor that reduces the retention rate of switches from a biologic originator (BO) to biosimilars (BS) in rheumatology. <h3>Objectives</h3> To identify the risk factors (RFs) and interventions strategies to reduce the NE in rheumatism and musculoskeletal diseases (RMDs), and more specifically in BS switches. <h3>Methods</h3> MEDLINE, Embase and Cochrane databases were systematically searched (inception to 15<sup>th</sup> November 2018) using relevant keywords: search1: "musculoskeletal diseases" and "nocebo" or "non-specific side effect" (NS-SE); search2: "biosimilars" and "nocebo" or "non-specific side effect". Inclusion criteria were: studies on pharmacological treatments, studies investigating RFs for NE or NS-SEs, studies specifically describing an intervention aimed to reduce NE. Studies on non-RMDs and fibromyalgia were excluded. <h3>Results</h3> Of 212 and 639 references screened respectively in search1 and search2, 151 duplications were deleted, 32 mentioning NE or equivalent were read in full text by 2 independent investigators and consensually selected. No study met inclusion criteria for NE risk factors: 6 studies investigated the RFs of discontinuation after switch to BS, 3 with etanercept (ETN), 3 with infliximab (IFX), one investigated risk factors of back switch (meaning return from BS ETN to BO ETN), one study analyzed a genetic factor of intolerance to methotrexate (MTX) in juvenile idiopathic arthritis (JIA) and one study assessed the RFs for overall discontinuation of biologics. Although contextual factors were mentioned, no study tested RFs on NE responders only. RFs for a negative outcome were low self-efficacy, small-size rheumatology department, early start of IFX BS after its introduction on the market. Only 5 studies met the inclusion criteria for specific interventions to reduce NE. One was about countermeasures used to reduce MTX intolerance in children with JIA: including covert dosing and taste masking, with no significant results. The other four studies aimed to reduce NE related to a switch: by a shared decision-making method (ETN, one study), another by a structured communication strategy (ETN, one study) and two by a standardized information (ETN, one study; IFX, one study). Rate of NS-SE was mentioned in 3 studies, and the outcome (NS-SE rate compared to NE-SE rate of control group) was mentioned in only 2 studies. However, the assessment of intervention efficacy was not possible, since comparison was performed with historical cohorts. <h3>Conclusion</h3> Although nocebo effect is an important issue in rheumatology, especially as an explicative factor for limiting the retention rate when switching from biologic originators to biosimilars, its risk factors and intervention strategies to prevent it are poorly known. Our results encourage studies to better understand the risk factors associated with nocebo effect and the means to reduce it, particularly in the context of switches from bio-originators to biosimilars. <h3> Disclosure of Interests</h3> None declared