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Background: Real-world evidence supporting a safe and effective transition from rituximab originator (RTX-O) to its biosimilars (RTX-B) in autoimmune rheumatic diseases (ARDs) is still limited. Objectives: The primary aims of this study were to evaluate the long-term persistence of RTX-B after the non-medical switch (NMS) from RTX-O in ARD patients, and to explore the RTX-B safety profile. The secondary aims were to evaluate the impact of different factors on RTX-B drug retention rate (DRR) and to identify any factors associated with RTX-B discontinuation. Design: Retrospective observational study. Methods: We included consecutive ARD patients undergoing NMS from RTX-O to GP2013 or CT-P10 from January 2018 to December 2020. RTX-B DRR was estimated by Kaplan–Meier plot analysis and compared according to different factors by the Log-rank test; the Cox proportional hazard model was used to detect factors associated with RTX-B discontinuation in the first 36 months. Results: We enrolled 181 patients switching to RTX-B: GP2013 in 143 (79.0%) cases and CT-P10 in 38 (21.0%). The estimated DRR for RTX-B was 81.5% at 12 months, 80.6% at 24 months, and 77.4% at 36 months. The incidence of adverse events with RTX-B was 12.6/100 patients/year. In the Log-rank test, no statistically significant differences were observed in the RTX-B DRR according to sex (p = 0.171), ARD diagnosis (p = 0.281), and concomitant immunosuppressive therapy (p = 0.054); on the contrary, patients on GP2013 showed a higher DRR than those on CT-P10 (p < 0.001). In the Cox proportional hazard analysis, the switch to CT-P10 was associated with a higher probability of stopping treatment (hazard ratio, 1.83 (confidence interval, 1.10–3.04), p = 0.02). Conclusion: NMS to RTX-B is associated with a high chance of retaining the drug for up to 36 months, irrespective of the diagnosis. GP2013 showed a higher retention rate than CT-P10. [ABSTRACT FROM AUTHOR]

Aseptic abscesses syndrome is a rare but increasingly recognized disease that falls within the spectrum of autoinflammatory disorders. Here, we describe the case of a patient who presented with abdominal pain and fever, along with multiple abdominal and extra-abdominal abscesses, in the absence of underlying hematologic, autoimmune, infectious, or neoplastic conditions. Initially, the patient responded to glucocorticoids, but experienced several flares upon discontinuation, leading to the initiation of treatment with a TNFα inhibitor. After 5 years, an attempt to discontinue treatment resulted in a new flare of the disease. Remission was eventually achieved with a biosimilar TNFα inhibitor, albeit requiring shortened infusion intervals.

Objective: to confirm the efficacy and safety of levilimab in patients with rheumatoid arthritis (RA) switched from other interleukin 6 receptor inhibitors (iIL6R) for non-medical reasons.Patients and methods. A retrospective analysis of data from the register of patients with RA who during the COVID-19 pandemic were switched from foreign iIL6Rs to the Russian drug levilimab. Treatment regimens with levilimab in combination with synthetic diseasemodifying antirheumatic drugs (sDMARDs) and/or glucocorticoids (GCs) were used, as well as a monotherapy regimen in case of DMARDs intolerance.Results and discussion. In 150 patients with RA, a successful non-medical switch to levilimab was demonstrated with the preservation and intensification of the clinical effect achieved on previous therapy with iIL6R. After switching to levilimab, the DAS28-CRP index decreased by an average of 0.098 at 3 months and by 0.25 at 6 months (p=0.214 for both time points). There was a decrease in the proportion of patients with elevated levels of CRP, as well as with high RA activity. In a number of patients who showed high efficacy of levilimab, it became possible to reduce the dose or number of DMARDs, as well as cease GCs intake. Good tolerability and a favorable safety profile of levilimab were noted, including in relation to the new coronavirus infection that developed during therapy.Conclusion. Therapy with Russian iIL6R levilimab is effective and safe, including in patients switched from other drugs for non-medical reasons, as well as in relation to the novel coronavirus infection that developed during therapy.

Randomized controlled trials showed high comparability of biosimilar rituximab (bs-RTX) GP2013 to biologic originator RTX (bo-RTX). Data on effectiveness of switching from bo-RTX to bs-RTX, starting therapy with bs-RTX, and bs-RTX drug survival in real-world setting are sparse. To explore long-term drug effectiveness and survival of bs-RTX GP2013 in rheumatoid arthritis (RA) patients both naïve to and mandatory switched from bo-RTX, and to clarify reasons for treatment cessation. Retrospective observational cohort study including RA outpatient clinic patients treated with bs-RTX between 2018 and 2021 in Norway. Patients were examined and monitored using recommended measures for disease activity and patient-reported outcomes (PROs). For description of population medians and interquartile range were used. Difference between observation times was assessed with Signed-Rank test, drug survival with Kaplan–Meier survival analysis. Reasons for discontinuation were ascertained. Among 110 patients, at baseline, 88 were mandatory switched from bo-RTX and 22 were RTX-naïve. During 2-year follow-up, disease activity and PROs measures remained stable in switchers subgroup and improved in subgroup starting bs-RTX for the first time. Overall drug survival was 80.0% after 1 year and 57.7% after 2 years and was significantly higher in bs-RTX-switched than in bs-RTX-naïve patients (p = 0.036). Two most frequently reported reasons for drug discontinuation were remission (38.6%) and doctor's decision (27.1%). RA patients treated with bs-RTX had satisfactory treatment response and drug retention rates which supports equivalence of bs-RTX GP2013 to bo-RTX, both in patients naïve to and mandatory switched from bo-RTX. [ABSTRACT FROM AUTHOR]

Project NORTH compared real-world clinical and economic outcomes in Swedish patients with inflammatory bowel disease (IBD) who switched from originator infliximab to its biosimilar. Data from electronic medical records and Swedish national registries were linked. Switchers (patients switching from originator infliximab to its biosimilar between 1 April 2014, and 31 December 2017) and non-switchers (patients who received originator infliximab and did not switch to a biosimilar by 31 December 2017) were followed up until 31 October 2019. Baseline concomitant medication use, disease duration, and inflammatory markers were lower among switchers than non-switchers. At 6 months, the proportion of patients with stable disease was higher among switchers than non-switchers (71/109 [65%] vs 54/107 [50%]; p =.0385); differences were not significant in subsequent follow-ups. At 6 and 24 months, 98% and 93% of switchers, respectively, used concomitant medications versus 96% and 79% of non-switchers. Throughout the study, all-cause treatment discontinuation occurred in 74 (67%) switchers and 105 (95%) non-switchers. At 36-months, mean (SD) number of IBD-related in-patient care days was higher among non-switchers (2.95 [4.71]) than switchers (1.40 [4.20]), as were total medical costs (€16,740 vs €3,872). No substantial differences in clinical outcomes or healthcare resource utilization were observed between switchers and non-switchers. Several analyses indicate that non-switchers might have more poorly controlled/severe disease than switchers at baseline. Overall, numerous difficulties might arise when executing a high-quality, real-world study, including possible selection bias for patients with better disease control for NMS, limiting the generalizability of the results. [ABSTRACT FROM AUTHOR]

Clinical data on the efficacy and safety of non-medical switch between adalimumab(ADA) biosimilars are limited. The aim of this study was to evaluate medium-term clinical efficacy, drug sustainability and safety comparing non-medical switches from the originator to biosimilar ADA, and between ADA biosimilars. 276 consecutive patients on maintenance ADA therapy (n = 205 Crohn's disease, n = 71 ulcerative colitis) were included. Data on clinical efficacy, biomarkers and adverse events were collected at four time points: 8–12 weeks prior switch, at baseline/switch, 8–12 weeks and 20–24 weeks after switch. Drug survival was evaluated after a median 40(IQR:35–42) weeks follow-up. A total 174 patients underwent a non-medical switch from the originator to a biosimilar, and 102 patients had a biosimilar-to-biosimilar switch. No significant difference was found in clinical remission rates at any time point in patients switching from originator to biosimilar(87.3%/88.5%/86.5%/85.7%) or biosimilar to biosimilar(74.5%/78.4%/85.3%/79.8%). Mean C-reactive protein levels remained unchanged in both cohorts(p = 0.856 and p = 0.525). Drug survival was similar between the two cohorts with a probability of 91.6%(SE: 2.2) and 87.0%(SE:3.4) to stay on drug after 40 weeks(log-rank:0.96; p = 0.327). Five cases of injection related adverse events were reported. Clinical benefit was sustained following non-medical switch from originator to biosimilar, or between biosimilars in adalimumab treated IBD patients. [ABSTRACT FROM AUTHOR]

Introduction: To examine the prevalence rates of biosimilar discontinuation and switchback to the originator tumor necrosis factor alpha (TNF) inhibitors following non-medical switch (NMS) in patients. Methods: Real-world studies reporting biosimilar discontinuation and switchback rates following NMS published between January 2012 and August 2018 were identified through a systematic literature review. A meta-analysis estimated the annualized discontinuation and switchback rates. A subsequent meta-analysis assessed annualized incremental discontinuation rate among studies reporting both discontinuation rates in patients who underwent an NMS (switchers) and patients who remained on originators (non-switchers). Results: A total of 66 publications were identified: 31 in gastroenterology, 32 in rheumatology, and 3 in both. Half of the studies reported switchback rates; only 9 studies reported discontinuation rates for both switchers and non-switchers. Across studies, the mean/range sample size of the NMS patient population was 136/9–1641; mean/range follow-up was 10/3–24 months. Annualized biosimilar discontinuation rate was 21% (95% confidence interval [CI] 18%, 25%). Switchback rate was 14% (95% CI 10%, 17%) among all NMS patients and 62% (95% CI 44%, 80%) among discontinuers. The mean/range sample size of switchers and non-switchers was 344/89–1621 and 768/19–2870, respectively; mean/range follow-up was 11/6–18 and 12/6–8 months, respectively. Annualized incremental biosimilar discontinuation rate was 18% (95% CI 4%, 31%). Conclusion: Biosimilar discontinuation was found to be prevalent among patients who underwent an NMS from an originator TNF inhibitor to its biosimilar(s) in the real world. In addition, switchback to the originator TNF inhibitors was common following biosimilar discontinuation. Careful consideration is necessary when switching patients already on an originator TNF inhibitor to its biosimilar(s). Main limitations included the heterogeneity of the studies and the limited comparability of the data. [ABSTRACT FROM AUTHOR]

Introduction: A non-medical switch is a change to a patient’s medication regimen for reasons other than lack of clinical response, side-effects or poor adherence. Specialist physicians treat complex patients who may be vulnerable to non-medical switching. Objectives: To evaluate specialist physicians’ perceptions regarding the frequency of non-medical switch requests, and the impact on their patients’ outcomes and healthcare utilization. Methods: An online survey of randomly sampled physicians spending ≥10% of time providing patient care and having received ≥1 non-medical switch request during the prior 12-months. Results: Among 404 specialist physicians surveyed, non-medical switch requests were reported as very frequent or frequent by 35.0% of oncologists (for injectable cancer agents) and up to 80.3% of endocrinologists (for injectable anti-hyperglycemics). Respondents reported decreased medication effectiveness (25.0% of oncologists to 75.0% of dermatologists) and increased side-effects (32.5% of oncologists to 66.7% of psychiatrists). Most specialists reported very frequent or frequent increases in non-office visits (52.5% of oncologists to 75.3% of endocrinologists) and calls with pharmacies (57.5% of oncologists to 80.5% of rheumatologists) due to non-medical switching. Conclusions: Receipt of non-medical switching requests were common among specialist physicians. Non-medical switching may lead to negative effects on patient care and require increased healthcare utilization.

Biosimilars are more affordable versions of previously approved biopharmaceuticals that are designed to reduce healthcare expenditure and increase patient access to this therapeutic class. To achieve their economic potential, many European countries have started to switch patients from reference drugs to biosimilars. The purpose of this article is to provide a comprehensive perspective on the biosimilar switching controversy, to assess interchangeability regulation and switching policies, and to review current evidence on switching and immunogenicity in the context of inflammatory rheumatic conditions. Patients and physicians feel uncertain about switching highly complex and difficult-to-replicate biosimilars of monoclonal antibodies due to a theoretical risk of increased immunogenicity, especially in extrapolated indications and in a multiple switch scenario involving various biosimilars. However, past experience with smaller biosimilars (somatropin, filgrastim, epoetin), the high standards required for approval of biosimilars of monoclonal antibodies in the European market, and current evidence on switching to infliximab and etanercept biosimilars (especially CT-P13 and SB4) are reassuring. Furthermore, no increased immunogenicity has been reported after switching to biosimilars. Decisions on switching and interchangeability are not covered by the European Medical Agency (EMA) guidelines and are left to individual European states, as opposed to the U.S. Food and Drug Administration (FDA), which has set standards to assess interchangeability. In summary, current knowledge is in favour of switching to biosimilars but the authors consider that this should be a physician-led decision with the active contribution of patients and hospital pharmacists to the pharmacovigilance chain.

Introduction: A non-medical switch is a change to a patient's medication regimen for reasons other than lack of clinical response, side-effects or poor adherence. Specialist physicians treat complex patients who may be vulnerable to non-medical switching. Objectives: To evaluate specialist physicians' perceptions regarding the frequency of non-medical switch requests, and the impact on their patients' outcomes and healthcare utilization. Methods: An online survey of randomly sampled physicians spending ≥10% of time providing patient care and having received ≥1 non-medical switch request during the prior 12-months. Results: Among 404 specialist physicians surveyed, non-medical switch requests were reported as very frequent or frequent by 35.0% of oncologists (for injectable cancer agents) and up to 80.3% of endocrinologists (for injectable anti-hyperglycemics). Respondents reported decreased medication effectiveness (25.0% of oncologists to 75.0% of dermatologists) and increased side-effects (32.5% of oncologists to 66.7% of psychiatrists). Most specialists reported very frequent or frequent increases in non-office visits (52.5% of oncologists to 75.3% of endocrinologists) and calls with pharmacies (57.5% of oncologists to 80.5% of rheumatologists) due to non-medical switching. Conclusions: Receipt of non-medical switching requests were common among specialist physicians. Non-medical switching may lead to negative effects on patient care and require increased healthcare utilization. [ABSTRACT FROM AUTHOR]

Background: Non-medical switching (NMS) is defined as switching to a clinically similar but chemically distinct medication for reasons apart from lack of effectiveness, tolerability or adherence. Objective: To update a prior systematic review evaluating the impact of NMS on outcomes. Data sources: An updated search through 10/1/2018 in Medline and Web of Science was performed. Study selection: We included studies evaluating ≥25 patients and measuring the impact of NMS of drugs on ≥1 endpoint. Data extraction: The direction of association between NMS and endpoints was classified as negative, positive or neutral. Data synthesis: Thirty-eight studies contributed 154 endpoints. The direction of association was negative (n = 48; 31.2%) or neutral (n = 91; 59.1%) more often than it was positive (n = 15; 9.7%). Stratified by endpoint type, NMS was associated with a negative impact on clinical, economic, health-care utilization and medication-taking behavior in 26.9%,41.7%,30.3% and 75.0% of cases; with a positive effect seen in 3.0% (resource utilization) to 14.0% (clinical) of endpoints. Of the 92 endpoints from studies performed by the entity dictating the NMS, 88.0%were neutral or positive; whereas, only 40.3%of endpoints from studies conducted separately from the interested entity were neutral or positive. Conclusions: NMS was commonly associated with negative or neutral endpoints and was seldom associated with positive ones.

Background: Non-medical switching (NMS) is defined as switching to a clinically similar but chemically distinct medication for reasons apart from lack of effectiveness, tolerability or adherence. Objective: To update a prior systematic review evaluating the impact of NMS on outcomes. Data sources: An updated search through 10/1/2018 in Medline and Web of Science was performed. Study selection: We included studies evaluating ≥25 patients and measuring the impact of NMS of drugs on ≥1 endpoint. Data extraction: The direction of association between NMS and endpoints was classified as negative, positive or neutral. Data synthesis: Thirty-eight studies contributed 154 endpoints. The direction of association was negative (n = 48; 31.2%) or neutral (n = 91; 59.1%) more often than it was positive (n = 15; 9.7%). Stratified by endpoint type, NMS was associated with a negative impact on clinical, economic, health-care utilization and medication-taking behavior in 26.9%,41.7%,30.3% and 75.0% of cases; with a positive effect seen in 3.0% (resource utilization) to 14.0% (clinical) of endpoints. Of the 92 endpoints from studies performed by the entity dictating the NMS, 88.0%were neutral or positive; whereas, only 40.3%of endpoints from studies conducted separately from the interested entity were neutral or positive. Conclusions: NMS was commonly associated with negative or neutral endpoints and was seldom associated with positive ones. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to describe real-world experiences following a non-medical switch among adults with type 2 diabetes mellitus (T2DM) in the United States.Methods: For this cross-sectional study, patients with T2DM (N = 451) provided data on demographics, and how a non-medical switch of their anti-hyperglycemic agent (AHA) affected their general health, HbA1c levels and medication management, via an Internet-based survey. Patients self-reported their level of satisfaction with the original medication and emotional reactions to the non-medical switch. Patients who recently experienced a non-medical switch of their AHA(s) (n = 379) were asked about the consequences of switching and their satisfaction with the switch (vs. the original) medication.Results: Patients most frequently reported feeling very/extremely frustrated, surprised, upset and angry in reaction to a non-medical switch. Patients were somewhat satisfied with their original medication. Between 20% and 30% of patients reported the non-medical switch had a moderate/major effect on their general health, diabetes, mental well-being and control over their health. The blood glucose levels of recent switchers were somewhat/much worse (20.7%) and medication management was somewhat/much worse (12.9%) on the switch (vs. the original) medication. Some recent switchers reported old symptoms returning (7.7%) and experiencing new side-effects (14.2%).Conclusions: Approximately one in five patients reported a moderate/major negative impact on their blood glucose level, diabetes, mental well-being, general health and control over their health following a non-medical switch. Findings suggest that a non-medical switch may have unintended negative health consequences and results in considerable burden across multiple domains for a sizeable minority of patients with T2DM. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, non-medical switching of biological medication may provoke nocebo effects due to unexplained deterioration of therapeutic benefits. Indication extrapolation, idiosyncratic reactions, and interchangeability remain challenged in clinical practice after biosimilar approval by the European Medicines Agency. The principle of “first do no harm” may be challenged in a patient when switching from originator to biosimilar biological.Aim: To describe the 1-year results of a pragmatic study on infliximab biosimilar implementation in immune-mediated inflammatory disease patients on the basis of shared decision-making under effectiveness and safety monitoring.Methods: Inflammatory bowel disease and rheumatology patients on infliximab originator were converted to infliximab biosimilar after providing informed consent. Nocebo response patients were monitored after switch back to originator. Linear mixed models were used to analyze continuous endpoints on effectiveness and laboratory outcomes to determine significance (P ≤ 0.05) of change over time after switching.Results: After inviting 146 patients, a group of 125 patients enrolled in the project over time, respectively, 73 Crohn’s disease, 28 ulcerative colitis, nine rheumatoid arthritis, ten psoriatic arthritis, and five ankylosing spondylitis patients. No statistically significant changes in effectiveness and safety were observed in any of the indications after a median of 4 infusions in 9 months of study. An overall nocebo response of 12.8% was found among the patients during a minimal observation period of 6 months after the transition to biosimilar infliximab. The overall nocebo response rate did not differ between the studied indications.Conclusions: In inflammatory bowel disease and rheumatological patients, similar effectiveness and safety were demonstrated on the transition into infliximab biosimilar. In our series, patient empowerment and registration of treatment outcomes delineated biosimilar transition, an approach that hypothetically could reduce nocebo response rates which are relevant to account for regarding biosimilar implementation. [ABSTRACT FROM AUTHOR]

Background: Few data are available on subjective disease control and perception of adverse events (AEs) during switching from original anti-TNF agents to biosimilars., Research Design and Methods: Hungarian patients with inflammatory bowel disease were interviewed after a mandatory non-medical switch from an infliximab (IFX) originator to a biosimilar GP1111 or from an adalimumab (ADA) originator to a biosimilar GP2017. Drug choice was based on patient's and physician's decision. Subjective efficacy was measured using a 10-point scale, and AEs were assessed. Difference in efficacy before and after the switch was compared within and between the drugs., Results: Seventy-three ADA and 106 IFX switching patients were interviewed. Subjective efficacy of IFX biosimilar was rated lower compared to IFX originator (8.72 ± 1.68 vs. 7.77 ± 2.34; p  = 0.001). The ADA biosimilar was rated higher than its originator (9.02 ± 1.61 vs. 8.42 ± 1.93; p  = 0.017). Patients receiving ADA biosimilar were more satisfied with the new treatment compared to IFX ( p  = 0.032). The incidence of new AEs was 85% in the ADA and 55% in the IFX group (1.79 vs. 0.93 AEs per patient, respectively, p  < 0.001)., Conclusion: Subjective efficacy of switching to a biosimilar was proven in case of ADA, while reduced efficacy was experienced with IFX biosimilar. Perception of AEs was high and varied between biosimilars.

Objective: To evaluate current knowledge of the impact of non-medical switching on clinical and economic outcomes, resource utilization and medication-taking behavior.Methods: The literature was searched (Medline and Web of Science, January 2000-November 2015) to identify United States' studies evaluating ≥25 patients and measuring the impact of non-medical switching of drugs (switching to a chemically distinct but similar medication for reasons other than lack of clinical efficacy/response, side effects or poor adherence) on ≥1 clinical, economic, resource utilization or medication-taking behavior outcome. The direction of association between non-medical switching and outcomes was classified as negative or positive if a statistically significant worsening or improvement was reported, or neutral if no significant difference was observed.Results: Twenty-nine studies contributed 96 outcomes (60.4% clinical; 21.9% resource utilization; 13.5% economic; 4.2% medication-taking behavior) within six disease categories (cardio-metabolic, immune-mediated, acid suppression, psychiatric, hormone replacement therapy and pain). The direction of association was more frequently negative (33.3%) or neutral (55.2%) than it was positive (11.5%). Stratified by outcome type, non-medical switching was negatively associated with clinical, economic, healthcare utilization and medication-taking behavior outcomes in 20.7%, 69.2%, 38.1% and 75.0% of cases, respectively; and positively in only 4.8%-17.2% of outcomes subgroups. Of 32 outcomes in patients demonstrating stable/well controlled disease, 68.8% and 31.3% had a negative and neutral direction of association. In patients without demonstrated disease stability, outcomes were negatively, neutrally and positively impacted by non-medical switching in 15.6%, 67.2% and 17.2% of 64 outcomes.Limitations: Our inability to evaluate specific disease state categories and studies/outcomes received equal weight regardless of sample size or magnitude of effect.Conclusions: Non-medical switching was more often associated with negative or neutral effects than positive effects on an array of important outcomes. Among patients with stable/well controlled disease, non-medical switching was associated with mostly negative effects. [ABSTRACT FROM AUTHOR]

These days, the use of biosimilars for the treatment of bio-naive patients is well established. However, the transition of patients being treated with a bio-originator to its biosimilar is still a topic of discussion. The main issue is which approach to use when initiating the non-medical transition. The first real-world examples contain both mandatory and non-mandatory approaches, resulting in a variety of acceptance and discontinuation rates. At this moment a non-mandatory approach, based on shared decision making, is preferred by international guidelines and the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. However, clear definitions of mandatory and non-mandatory are lacking, as a result of which these terms may be wrongly used in some studies. This article aims to provide an overview of transition approaches used in the Netherlands, and how the approach used relates to acceptance and discontinuation rates of the biosimilar., (© 2019 The Mediterranean Journal of Rheumatology (MJR).)