Objective. To evaluate drug survival, effectiveness, pharmacokinetics, immunogenicity, and safety in daily practice after transitioning treatment from original reference infliximab (Remicade [REM]) to a biosimilar infliximab (CT-P13 [Remsima; Inflectra]) in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.Methods. Of the initial 222 REM-treated patients, 192 agreed to transition to CT-P13 and were included in this multicenter prospective cohort study. Changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and changes in the CRP levels, infliximab trough levels, and anti-infliximab antibody levels were assessed after 6 months, and adverse events (AEs) were documented. Drug survival and prognostic factors were analyzed using Kaplan-Meier and Cox regression analyses.Results. During 6 months follow-up, 24% of the patients (n = 47) discontinued CT-P13. Thirty-seven patients restarted REM, 7 switched to another biologic drug, and 3 continued without a biologic drug. The DAS28-CRP remained stable from baseline to month 6, with a mean AE SD score of 2.2 AE 0.9 at baseline to 2.2 AE 0.8 at 6 months (difference of 0.0 [95% confidence interval (95% CI) -0.1, 0.2]). The BASDAI increased from a mean AE SD of 3.8 AE 2.0 at baseline to 4.3 AE 2.1 at 6 months (difference of +0.5 [95% CI 0.1, 0.9]). The CRP levels, infliximab trough levels, and anti-infliximab antibody levels did not change. Just prior to CT-P13 discontinuation, the DAS28-CRP components tender joint count and patient's global assessment of disease activity, as well as the BASDAI were increased compared to baseline. The most frequently reported AEs were arthralgia, fatigue, pruritus, and myalgia. A shorter REM infusion interval (hazard ratio: 0.77 [95% CI 0.62, 0.95]) at baseline was predictive of discontinuing CT-P13.Conclusion. In our cohort, one-fourth of patients discontinued CT-P13 during 6 months of follow-up, mainly due to an increase in the subjective features of the tender joint count and the patient's global assessment of disease activity and/or subjective AEs, possibly explained by nocebo effects and/or incorrect causal attribution effects.

Non-mandatory transitioning from originator ETN to biosimilar SB4 using a specifically designed communication strategy resulted in a slightly lower 6-month treatment persistence rate and smaller decreases in disease activity in the transition cohort compared to the historical cohort, but these differences were not considered clinically relevant.

BackgroundThe extracellular domains of cytokine receptors are released during inflammation, but little is known about the shedding of Toll-like receptors (TLR) and whether they can be used as diagnostic biomarkers.MethodsThe release of sTLR2 and sTLR4 was studied in in-vitro stimulations, as well as in-vivo during experimental human endotoxemia (n = 11, 2 ng/kg LPS), and in plasma of 394 patients with infections (infectious mononucleosis, measles, respiratory tract infections, bacterial sepsis and candidemia) or non-infectious inflammation (Crohn’s disease, gout, rheumatoid arthritis, autoinflammatory syndromes and pancreatitis). Using C-statistics, the value of sTLR2 and sTLR4 levels for discrimination between infections and non-infectious inflammatory diseases, as well as between viral and bacterial infections was analyzed.ResultsIn-vitro, peripheral blood mononuclear cells released sTLR2 and sTLR4 by exposure to microbial ligands. During experimental human endotoxemia, plasma concentrations peaked after 2 hours (sTLR4) and 4 hours (sTLR2). sTLR4 did not correlate with cytokines, but sTLR2 correlated positively with TNFα (rs = 0.80, P < 0.05), IL-6 (rs = 0.65, P < 0.05), and IL-1Ra (rs = 0.57, P = 0.06), and negatively with IL-10 (rs = -0.58, P = 0.06), respectively. sTLR4 had a similar area under the ROC curve [AUC] for differentiating infectious and non-infectious inflammation compared to CRP: 0.72 (95% CI 0.66-0.79) versus 0.74 (95% CI 0.69-0.80) [P = 0.80], while sTLR2 had a lower AUC: 0.60 (95% CI 0.54-0.66) [P = 0.0004]. CRP differentiated bacterial infections better from viral infections than sTLR2 and sTLR4: AUC 0.94 (95% CI 0.90-0.96) versus 0.58 (95% CI 0.51-0.64) and 0.75 (95% CI 0.70-0.80), respectively [P < 0.0001 for both].ConclusionssTLRs are released into the circulation, and suggest the possibility to use sTLRs as diagnostic tool in inflammatory conditions.

ObjectiveTo systematically review studies addressing prediction of successful dose reduction or discontinuation of a biologic agent in rheumatoid arthritis (RA).MethodsPubMed, Embase, and Cochrane Library databases were searched for studies that examined the predictive value of biomarkers for successful dose reduction or discontinuation of a biologic agent in RA. Two reviewers independently selected studies, and extracted data and assessed the risk of bias. A biomarker was classified as a “potential predictor” if the univariate association was either strong (odds ratio or hazard ratio >2.0 or <0.5) or statistically significant. For biomarkers that were studied multiple times, qualitative best‐evidence synthesis was performed separately for the prediction of successful dose reduction and discontinuation. Biomarkers that were defined in ≥75% of the studies as potential predictors were regarded as “predictor” for the purposes of our study.ResultsOf 3,029 nonduplicate articles initially searched, 16 articles regarding 15 cohorts were included in the present study. Overall, 17 biomarkers were studied multiple times for the prediction of successful dose reduction, and 33 for the prediction of successful discontinuation of a biologic agent. Three predictors were identified: higher adalimumab trough level for successful dose reduction and lower Sharp/van der Heijde erosion score and shorter symptom duration at the start of a biologic agent for successful discontinuation.ConclusionThe predictive value of a wide variety of biomarkers for successful dose reduction or discontinuation of biologic treatment in RA has been investigated. We identified only 3 biomarkers as predictors, in just 2 studies. The strength of the evidence is limited by the low quality of the included studies and the likelihood of reporting bias and multiple testing.

BackgroundIn blinded trials, transitioning from an innovator to a biosimilar has shown to be equivalent to maintenance on innovator biologic treatment in rheumatic diseases. However, data on open label transitioning to a biosimilar are scarce. Recently, we sequentially implemented two biosimilar transition projects (from innovator infliximab (REM) to biosimilar infliximab (CT-P13) and from innovator etanercept (ENB) to biosimilar etanercept (SB4)) in patients with a rheumatic disease using different communication strategies.ObjectivesTo investigate the impact of different communication strategies on the acceptance and persistence rates after transitioning from ENB to SB4 in 2016 and transitioning from REM to CT-P13 in 2015.MethodsAdult patients treated with REM or ENB were informed by letter about the request to transition to a biosimilar. Subsequently, patients were approached by telephone to ask whether they agreed. After the transition of REM to CT-P13 had finished, communication was enhanced for the transition of ENB to SB4 by 1) informing all patients at the same time directly followed by a national media item, 2) reporting that lower costs and fewer injection site reactions (demonstrated in a previous trial) were the reason for transitioning, 3) providing a “soft skills” training for rheumatology and pharmacy staff about how to assuage patient concerns regarding a biosimilar and how to act if a patient has objective or subjective health complaints (discuss possible nocebo response and incorrect causal attribution). Also, group think effects did not play a role during SB4 treatment (individual subcutaneous versus group intravenous administration). Transitioning patients were eligible for inclusion in the BIO-SWITCH study (switch REM to CT-P13) and BIO-SPAN study (switch ENB to SB4)1. Demographic, disease and treatment specific characteristics at baseline and disease activity and adverse events (AEs) during 6 months follow-up were collected.Results196 of 222 (88%) REM-treated patients and 636 of 643 (99%) ENB-treated patients transitioned to respectively CT-P13 and SB4 (delta 11%, 95% CI 7% to 16%). Until January 1st 2017, 479 of 636 (75%) patients gave informed consent for the BIO-SPAN study. Baseline characteristics were similar, except for disease duration and innovator treatment duration (both shorter in the BIO-SPAN cohort; p<0.01). Drug survival of patients on SB4 was adjusted for confounders greater than patients on CT-P13 (Figure 1; adjusted Hazard Rate 0.21, 95% CI 0.13 to 0.34). During 84 person-years of follow-up 47 patients discontinued CT-P13 (56/100 person-years; 26% due to inefficacy, 74% due to AEs). In contrast, 36 patients discontinued SB4 during 230 person-years of follow-up (16/100 person-years; 53% due to inefficacy, 42% due to AEs and 5% due to remission).ConclusionsUse of an enhanced communication strategy, together with more experience and absence of group think effects, resulted in much higher acceptance and persistence rates after open label shared decision making biosimilar transitio...