Case report: Breaking CNS immuno-privilege: TNFα-inhibitor triggers aseptic meningitis in a patient with rheumatoid arthritis.

Blood-brain barrier dysfunction might be driven by peripheral inflammation. TNFα inhibitors (TNF-αi) are occasionally associated with a wide spectrum of neurological immuno-mediated disorders. However, patients with systemic autoimmune disorders, including rheumatoid arthritis (RA), might be prone to develop further organ-specific, including central nervous system (CNS), autoimmunity. Here we report the case of a patient, affected by RA and treated with etanercept, who suddenly developed focal neurological symptoms. Cerebrospinal fluid, magnetic resonance imaging (MRI), and positron emission tomography (PET)/MRI findings are reported and support the diagnosis of TNF-αi -associated aseptic meningitis.

Frequency and outcomes of treatment dose escalation with biologics in moderate-to-severe psoriasis: a Swedish register study.

BACKGROUND: The advent of biosimilars may increase the frequency of dose escalation with biologics in psoriasis. OBJECTIVE: To explore the frequency and outcomes of dose escalation with adalimumab etanercept, and ustekinumab. METHODS: Data were extracted from DermaReg-Pso, a psoriasis register in Stockholm, Sweden. The main exposure was treatment, and the main outcome was dose escalation. We describe outcomes with dose escalation by estimating drug survival and changes in the Psoriasis Area and Severity Index (PASI). RESULTS: 554 patients had 946 treatment episodes with adalimumab, etanercept, or ustekinumab. The cumulative incidence of dose escalation was 4.1 per 100 treatment years. The Hazard Ratios (HRs) for dose escalation with ustekinumab vs adalimumab and ustekinumab vs etanercept were 1.93 (95% CI: 1.25-2.98), and 2.20 (95% CI: 1.42-3.41), respectively. After dose escalation, the HRs for treatment discontinuation with adalimumab and etanercept compared with ustekinumab were 3.10 (95% CI: 1.56-6.18) and 7.15 (95% CI: 3.96-12.94), respectively. PASI was higher after compared to before dose escalation for etanercept (p = 0.036), but not for adalimumab (p = 0.832) or ustekinumab (p = 0.300). CONCLUSIONS: Dose escalation was comparatively more frequent with ustekinumab than with adalimumab or etanercept; however, treatment discontinuation after dose escalation was more common with adalimumab and etanercept than ustekinumab.

Real-life data of etanercept efficacy and safety in juvenile idiopathic arthritis: a 24-month retrospective study at a single center.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of etanercept (ETA) use in juvenile idiopathic arthritis (JIA). METHODS: The 24-month data of patients with JIA on etanercept in a single center were evaluated retrospectively. Response to treatment was assessed according to 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and JIA-American College of Rheumatology (ACR) improvement criteria. Safety assessments were based on adverse event (AE) reports. RESULTS: The study included 152 patients with JIA. The mean age at diagnosis of JIA was 8.5 ± 4.4 years, and treatment with ETA started at a mean age of 11.1 ± 4.4 years. The mean duration of ETA use was 16 ± 11.1 months. The mean JADAS10 score at baseline was 18.5 ± 5.9. By the third month, it had reduced to 8.6 ± 6.6 and by the sixth month to 5.7 ± 6. By the twelfth month, the JADAS10 score was 4.9 ± 6.7, and by the twenty-fourth month, it had worsened to 7.3 ± 7.8. ACR50 response was achieved in 79.6% of patients at 3 months, 67.1% at 6 months, 79.3% at twelfth months, 70.7% at the twenty-fourth month. During ETA treatment, 10 patients required hospitalization for serious infections. CONCLUSION: Etanercept is a safe and effective option for patients with JIA. However, variations in response between JIA subtypes highlight the need for individualized treatment strategies.

Prescribing patterns and persistence of biological therapies for psoriasis management: a retrospective cohort study from Saudi Arabia.

BACKGROUND: Biological therapies are effective for psoriasis, but patient responses vary, often requiring therapy switching or discontinuation. OBJECTIVES: To identify physicians' prescribing patterns of biological therapies at a referral tertiary center in Saudi Arabia and assess the probability of biologic persistence following treatment initiation. METHODS: We conducted a retrospective study of biologic-naïve adult psoriasis patients who initiated therapy from October 2013 to July 2022 in Dammam. Descriptive statistics and a Kaplan-Meier analysis evaluated treatment persistence at 6, 12, 24, and 36 months. RESULTS: A total of 151 patients received adalimumab (n = 89), etanercept (n = 17), risankizumab (n = 30), ustekinumab (n = 14), and ixekizumab (n = 1). At 6 months, all therapies demonstrated 100% persistence. At 12 months, persistence was highest for ustekinumab (100%) and lowest for etanercept (88.2%). At 24 months, ustekinumab maintained 100% persistence, followed by risankizumab (96.6%), adalimumab (94.3%), and etanercept (76.4%). At 36 months, risankizumab had the highest persistence (96.6%), followed by adalimumab (83.1%), ustekinumab (78%), and etanercept (70.6%). The most common reasons for discontinuation were lack of effectiveness and intolerability. CONCLUSION: This study shows changing psoriasis treatment patterns with new therapies. Risankizumab demonstrated high long-term persistence, while etanercept and ustekinumab showed declining persistence, suggesting evolving treatment considerations.

Use of biologic therapies in the management of pyoderma gangrenosum: a systematic review.

Treatment of pyoderma gangrenosum (PG) is challenging due to the absence of standardized guidelines and the lack of evidence-based, effective treatment options. Here, we performed a systematic review to summarize the use of biologics and their efficacy in the treatment of PG. We searched PubMed/MEDLINE, EMBASE, and Cochrane electronic databases from their inception to September 22nd, 2022, and included 82 peer-reviewed studies with a total of 108 patients. Infliximab, adalimumab, and etanercept were the most utilized biologic therapies in the treatment of PG in 64.8% (70/108), 16.7% (18/108), and 11.1% (12/108) of the cases, respectively. With respect to treatment response, 88.9% (96/108) of the patients achieved complete resolution of PG with biologic therapies. The average number of days to improvement and resolution of PG treated after starting biologic therapies was 30 and 161, respectively. PG recurred in 15.5% (11/71) of those reported the outcome. Our study suggests that biologic therapies may be an attractive therapeutic option for PG with an excellent efficacy.

Tumor necrosis factor inhibitors enhance corticosteroid therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis linked to immune checkpoint inhibitors: a prospective study.

Introduction: Immune-related epidermal necrolysis (irEN), including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), represents a potentially lethal reaction to immune checkpoint inhibitors. An optimal treatment strategy remains undefined. This study evaluates the effectiveness and safety of combination therapy with corticosteroids and tumor necrosis factor inhibitors (TNFi) in treating irEN patients. Methods: In this single-center, prospective, observational study, patients with irEN received either corticosteroid monotherapy or a combination therapy of corticosteroids and TNFi (etanercept for SJS, infliximab for TEN). The primary endpoint was re-epithelization time, with secondary endpoints including corticosteroid exposure, major adverse event incidence, acute mortality rates, and biomarkers indicating disease activity and prognosis. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100051052). Results: Thirty-two patients were enrolled (21 SJS, 11 TEN); 14 received combination therapy and 18 received corticosteroid monotherapy. IrEN typically occurred after 1 cycle of ICI administration, with a median latency of 16 days. Despite higher SCORTEN scores in the combination group (3 vs. 2, p = 0.008), these patients experienced faster re-epithelization (14 vs. 21 days; p < 0.001), shorter corticosteroid treatment duration (22 vs. 32 days; p = 0.005), and lower prednisone cumulative dose (1177 mg vs. 1594 mg; p = 0.073). Major adverse event rates were similar between groups. Three deaths occurred due to lung infection or disseminated intravascular coagulation, with mortality rates for both groups lower than predicted. Potential risk factors for increased mortality included continuous reduction in lymphocyte subset counts (CD4+ T cells, CD8+ T cells, natural killer cells) and consistent rises in inflammatory markers (serum ferritin, interleukin-6, TNF-α). Re-epithelization time negatively correlated with body mass index and positively correlated with epidermal detachment area and serum levels of interleukin-6 and TNF-α. Conclusions: Corticosteroids combined with TNFi markedly promote re-epithelization, reduce corticosteroid use, and decrease acute mortality in irEN patients without increasing major adverse events, offering a superior alternative to corticosteroid monotherapy. Inflammatory markers and lymphocyte subsets are valuable for assessing disease activity and prognosis.

Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial.

OBJECTIVES: To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt. METHODS: CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score - C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups. RESULTS: Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=-0.204, (95% CI -0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%). CONCLUSION: Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104. TRIAL REGISTRATION NUMBER: NCT03649061. CTR PILOT APPROVAL BELGIUM: S59474, EudraCT number: 2017-004054-41.

Uveitis as predictor of disease flare after the first anti-TNF withdrawal in oligoarticular and polyarticular juvenile idiopathic arthritis: a multicentric Italian experience.

OBJECTIVES: TNF inhibitors (TNFi) have dramatically changed the prognosis of juvenile idiopathic arthritis (JIA), but it is not clear how and when to stop therapy. We aim to describe a multicentric cohort of JIA treated with adalimumab or etanercept who discontinued the treatment for persistent inactivity and to identify factors associated with relapse. METHODS: In a multicentric Italian retrospective cohort study, medical records of patients with oligoarticular and polyarticular JIA were evaluated if they stopped therapy for persistent inactivity after the first TNFi. RESULTS: 136 patients were enrolled (102 female, median age at onset 3 years (range 1-15), of whom 55.9% had oligoarticular JIA, 40.4% uveitis and 72.8% ANA positivity. Adalimumab (59.3%) and etanercept (40.7%) were started at a median age of 6 years (range 1-16), TNFi were discontinued after a median time of 30 months (range 6-90), increasing the interval (76.5%), reducing the dose (18.4%) and abrupt discontinuation (16.9%). 79.4% of patients relapsed after a median time of 5 months (range 0.5-66). Patients with uveitis relapsed earlier (log rank χ² 16.4 p<0.0001), while patients who lengthened the interval of administration showed a later relapse (log rank χ² 6.95 p=0.008). Uveitis (HR 2.11 CI 1.34-3.31), age at onset (HR 0.909 CI 0.836-0.987), duration of tapering (HR 0.938 CI 0.893-0.985) and to have a persistent oligoarticular JIA (HR 0.597 CI 0.368-0.968) are significant predictors of disease relapse (Mantel-Cox χ² 34.23 p<0.001). CONCLUSIONS: Younger age at onset, uveitis, duration of tapering, and non-persistent oligoarticular JIA seem to be independent risk factors for earlier relapse after the first TNFi withdrawal.

Merkel cell carcinoma associated with TNF inhibitor therapy: a systematic review of case reports.

A rare neuroendocrine skin cancer called Merkel cell carcinoma (MCC) primarily affects elderly people. The objective of this study is to comprehensively review the impact of immunosuppressive medications, particularly TNF inhibitors, on the emergence of MCC. METHODS: PubMed, Web of Science, Science Direct, and Cochrane Library were searched. Study articles were screened by title and abstract at Rayyan Qatar Computing Research Institute, then a full-text assessment was implemented. RESULTS: A total of eight case reports with 9 patients were included. Of the total population, seven were women and only two were men. Their age ranged from 31 to 73 years. More than half the population (5 cases) were being treated for rheumatoid arthritis. All received TNF inhibitors that were associated with the induction of MCC. CONCLUSION: We found that it is essential for physicians to explain potential cancer risks to patients before starting long-term immunosuppressive therapy and to conduct routine checks for MCC and other side effects. TNF inhibitors (infliximab, adalimumab, etanercept, and golimumab) were all associated with MCC development. Women constituted the majority of cases and most were elderly.

Efficacy, safety and immunogenicity of the biosimilar etanercept compared to the reference formulation original etanercept in patients with rheumatoid arthritis: An open-label, randomized, comparative, multicenter study.

BACKGROUND: The objective of this phase III clinical randomized trial was to establish the therapeutic equivalence of biosimilar etanercept (bio-etanercept) with original etanercept (O-etanercept) for patients diagnosed with rheumatoid arthritis. METHODS: The study (NCT04079374) enrolled patients with moderate to high disease activity rheumatoid arthritis. Enrolled patients were randomized 1:1 into 2 treatment groups, 1 receiving bio-etanercept (study drug) and the other receiving O-etanercept (comparator) at a dose of 25mg twice weekly, for 24 weeks. The primary efficacy endpoint was the number of patients with an ACR20 response after 24 weeks of treatment. Safety (adverse reaction/adverse event) and immunogenicity of both drugs were evaluated. RESULTS: Among 156 patients (79 in the bio-etanercept group and 77 in the O-etanercept group) who completed 24-week treatment and 4-week follow-up, 82.3% (65 patients) and 90.9% (70 patients) achieved an ACR20 response in the bio-etanercept and O-etanercept groups, respectively. There was no significant difference between the 2 groups (P = .16). No significant differences in the occurrence of adverse reactions/adverse events were found between the 2 groups regardless of severity (P = .63 for mild, P = .43 for moderate and P > .99 for severe). The development of antibodies in the bio-etanercept group was observed in 4 (5.1%; visit 6), 4 (5.0%; visit 9), and 3 (3.8%; visit 11) patients, and in 5 (6.4%), 5 (6.5%), and 3 (4.1%) patients in the O-etanercept group. The differences between the 2 groups were not significant (P > .99). CONCLUSIONS: This study showed that bio-etanercept was equivalent to the reference formulation.

Comparison of disease-modifying anti-rheumatic drugs and hyperbaric oxygen therapy in the experimental model of rheumatoid arthritis in rats.

In this study, we wanted to investigate the effectiveness of combining disease-modifying anti-rheumatic drugs (DMARD) with hyperbaric oxygen therapy (HBOT) in reducing inflammation in a rheumatoid arthritis (RA) model using rats. We divided 56 male Sprague-Dawley rats into seven groups and induced RA using complete Freund's adjuvant. Some groups received HBOT, whereas others were given etanercept or leflunomide. We started the treatment on the 10th day after inducing RA and continued it for 18 days. To evaluate the effectiveness of the treatments, we measured paw swelling and used X-rays to examine the joints before and after the treatment. We also analysed the levels of two inflammatory markers, tumour necrosis factor (TNF)-α and interleukin (IL)-1ß, using an enzyme-linked immunosorbent assay. Additionally, we conducted histological analysis and assessed the expressions of anti-IL-1ß and anti-TNF-α antibodies. All the treatment groups showed a significant decrease in arthritis scores, paw swelling and levels of TNF-α and IL-1ß. The X-ray images revealed improvements in joint structure, and the histopathological analysis showed reduced inflammation and collagen abnormalities. Combining DMARD with HBOT had similar effects to individual therapies, suggesting a cost-effective and potentially safer approach for improving outcomes in rats with RA.

Newer Therapies in Rheumatology.

Seven of the 11 newer medications recently or soon to be approved to treat rheumatologic diseases discussed in this article are biologic agents and reflect the current ability of science to target specific components of the immune system. The other agents are molecules that are directed against specific immune pathway targets as well. All have shown superiority to placebo and in some cases have been compared to currently accepted therapies. Safety issues are generally centered around infections due to the immune-interrupting nature of these therapies.

The Safety Profiles of Adalimumab, Infliximab, Etanercept, Secukinumab and Ustekinumab in Psoriasis - A 30-month Observational Cohort Prospective Study of Adverse Events in Biologic Therapy.

BACKGROUND: Although biologic agents are very effective, long-term comparative studies demonstrating their safety relative to one another are still lacking. METHODS: A total of 124 patients with psoriasis were followed up for 30 months; 74 received anti-TNF-alpha inhibitors (adalimumab, etanercept, infliximab), 33 were on ustekinumab, and 17 were treated with secukinumab. The rates of adverse events in these groups were recorded and statistically analyzed. RESULTS: Infliximab-treated patients showed a high occurrence of asymptomatic, but increased liver enzymes, fatigue, and respiratory as well as dermatologic infections. Adalimumab-treated patients were more often affected by musculoskeletal disorders and infections of all types. Patients treated with secukinumab presented with higher rates of cardiovascular disorders as well as respiratory and dermatologic infections. The group receiving etanercept was more often diagnosed with musculoskeletal and reproductive disorders, specifically menstrual disorders. The rates of therapy discontinuation and serious adverse events did not reach statistically significant values. CONCLUSION: A higher incidence of adverse events was observed among adalimumab-, and infliximab-treated patients, with ustekinumab found to have the safest profile. Our results demonstrate that a personalized approach, including evaluation of a patient's risk profile, is necessary before commencing a biologic. Further research is warranted to confirm the findings of our study.

Charting the Etanercept Journey: Tracing Cost Dynamics in Poland's Off-Patent Market from Reference Drug Rivalry to Biosimilar Monopoly.

OBJECTIVES: To evaluate the pricing of etanercept (ETN) reference and biosimilar drugs in a changing competitive to monopolized market. METHODS: We conducted a comprehensive, retrospective analysis of ETN market competition, specifically changes in tender price based on shifts in market monopoly, including the effects on cost evolution, in the off-patent market in Poland. We included a total of 473 tenders for ETN purchase in dedicated biologic drug reimbursement programs, covering both pre-filled syringes and automatic injectors. This study covers the timeframe from November 2017 to December 2023, throughout which we evaluated a unique setting of ETN market re-monopolization from the perspective of payer, hospital and patient benefits resulting from changing cost calculations. RESULTS: Between 2017 and 2022, Erelzi was recorded as having the largest total tender volume (59%), with a mean price [per ETN daily defined dose (DDD)] of €7.28, followed by Enbrel (31%, €8.34) and Benepali (10%, €9.45), respectively. Over the last 6 months of waning market competition, the mean price for winning bids was estimated at €5.69. After market re-monopolization by an ETN biosimilar, the mean price of winning bids increased to €8.09, and continued to increase (€9.71) in the last 6 months of available follow-up. In contrast to the competitive era, no significant relationship between tender volume and winning price was recorded after re-monopolization. In the most recent tenders, mean ETN prices increased up to €15.82, nearly tripling the lowest prices of the competitive market period. In the early re-monopolization market, mean annual treatment cost per patient is estimated at over €3800, which exceeds therapy costs in the prior competitive market years, and is expected to increase to over €6200 based on the most recent tenders. On a healthcare system level, this corresponds to over €3.42 million excess costs due to market monopoly. Higher ETN prices resulted in downstream failure of regulatory incentives to promote affordable biologics. Due to higher pricing, hospitals lost over an estimated €2.52 million, with possible risk of treatment restrictions. For the same reason, the public payer achieved comparable savings, allowing for partial coverage of higher reimbursement expenses. CONCLUSIONS: This nation-level scenario of market re-monopolization by a biosimilar drug confirms net loss and excess costs for the healthcare payer, as can be expected from economic theory. The upwards drug repricing and restriction of treatment availability occurs much more rapidly than the decrement in a period of market competition.

Efficacy of switching from originator etanercept to biosimilar YLB113 in real-world patients with rheumatoid arthritis: A retrospective 12 months follow-up study.

Purpose: To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Methods: Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. Results: There was no significant difference in the DAS28 at baseline and 12 months after switching (p = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor (p = .04) and DAS28 (p < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor (p = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. Conclusions: RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.

Reduction of biologic pricing following biosimilar introduction: Analysis across 57 countries and regions, 2012-19.

OBJECTIVE: To evaluate the impact of the entry of biosimilars on the pricing of eight biologic products in 57 countries and regions. METHODS: We utilized an interrupted time series design and IQVIA MIDAS® data to analyze the annual sales data of eight biologic products (adalimumab, bevacizumab, epoetin, etanercept, filgrastim, infliximab, pegfilgrastim, and trastuzumab) across 57 countries and regions from January 1, 2012, to December 31, 2019. We examined the immediate and long-term changes in biologics ex-manufacturer pricing following the entry of biosimilars to the market. RESULTS: Following the entry of biosimilars, the average price per dose of biologic product was immediately reduced by $438 for trastuzumab, $112 for infliximab, and $110 for bevacizumab. The persistent effect of biosimilars' market entry led to further reductions in price per dose every year: by $49 for adalimumab, $290 for filgrastim, $21 for infliximab, and $189 for trastuzumab. Similarly, we analyzed the impact of biosimilars on four biologics' prices in the US, where the prices of three biologics significantly decreased every year, with filgrastim, pegfilgrastim, and infliximab decreasing by $955, $753, and $104, respectively. CONCLUSIONS: The introduction of biosimilars has significantly reduced the prices of biologics both globally and in the US. These findings not only demonstrate the economic benefits of increasing biosimilar utilization, but also emphasize the importance of biosimilars in controlling healthcare costs. Policies should aim to expand the availability of biosimilars to counteract the exponential growth of medical spending caused by the use of biologics.

Outcomes after anti-tumour necrosis factor originator to biosimilar switching in children and young people with juvenile idiopathic arthritis in the UK: a national cohort study.

BACKGROUND: For cost-saving purposes, children and young people with juvenile idiopathic arthritis (JIA) are being switched (for non-medical reasons) from biological originators to biosimilars. Here, we aimed to investigate those who switched from an anti-tumour necrosis factor (TNF) originator to a biosimilar, regarding drug survival and disease activity, compared with a matched cohort who continued the originator. METHODS: This analysis included all patients in the UK JIA Biologics Register switching directly from an anti-TNF originator to a biosimilar of the same product. All patients were matched (age, sex, disease duration, calendar year of when patients started originator therapy, line of therapy, and International League of Associations for Rheumatology [ILAR] category) to patients continuing the originator. For those matched successfully, a Cox proportional hazard model assessed whether drug persistence differed between those who switched compared with those who continued the originator. Overall change in the 71-joint juvenile arthritis disease activity score and the proportion of patients with a clinically important worsening score (by ≥1·7 units) after 6 months was compared between cohorts. This analysis was designed to address a priority research area set by our patient partners. FINDINGS: There were 224 children and young people with non-systemic JIA (139 [62%] were female, and 85 [38%] were male) identified as switching from a biological originator to a biosimilar of the same product from Jan 1, 2017, to July 7, 2023. 143 (64%) patients were originally on adalimumab, 56 (25%) on etanercept, and 25 (11%) on infliximab. Of these, 164 patients were matched successfully to those continuing the originator. There was no evidence that patients switching were more likely to stop treatment compared with those continuing the originator, with a hazard ratio of 1·46 (95% CI 0·93-2·30). Of the 51 patients in the biosimilar group who stopped treatment, 18 (35%) switched back to the originator (14 in the first year), 28 (55%) started a different biological drug, and five (10%) discontinued all treatment by the last follow-up. Of the 87 matched patients with available disease activity, there was no evidence that JADAS-71 worsened more after 6 months, with an odds ratio of 0·71 (95% CI 0·34-1·51; p=0·38). INTERPRETATION: In this matched comparative effectiveness analysis, children and young people with JIA switched from originators to biosimilars. Disease activity was similar between patients switching compared with those continuing the originator. Three quarters of patients were still receiving their biosimilar after 1 year, with switching back to originator uncommon, at only 9% after 1 year, suggesting good tolerability of non-medical switching in this patient population. This information is reassuring to clinicians and patients regarding the effect of non-medical biological switching. FUNDING: British Society for Rheumatology, Versus Arthritis, and National Institutes for Health Research Manchester Biomedical Research Centre.

Etanercept ameliorates chronic mild stress-induced depressive-like behavior in rats: Crosstalk between MAPK and STAT3 pathways and norepinephrine and serotonin transporters.

Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with daily functioning and quality of life. Despite decades of research, the pathophysiology of depression remains incompletely understood. The correlation between depression and inflammation has recently attracted considerable attention. This study investigated the potential antidepressant effect of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, utilizing a chronic mild stress (CMS) model in rats. Male Wistar rats were divided into two groups; one following a non-stressed protocol and the other a stressed protocol for 5 weeks. From the beginning of the third week, rats were treated either with saline daily or with etanercept twice a week (0.3 mg/kg, i.p.) or with fluoxetine daily (10 mg/kg, i.p) as a reference. Etanercept exhibited comparable effects to those of fluoxetine in counteracting CMS-induced behavioral manifestation in the forced swimming and splash tests. Etanercept also restored serotonin and norepinephrine levels to control values in the prefrontal cortex (PFC). Moreover, the current study verified the antioxidant and anti-inflammatory effects of etanercept. Interestingly, etanercept halted the expression of both norepinephrine and serotonin transporters in stressed rats. This could be attributed to abrogation of the p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 3 (STAT-3) pathways in the PFC. The findings of the present study contribute to the understanding of the potential of etanercept as an antidepressant and provide insights into the neurobiological mechanisms underlying its therapeutic effects.