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.

The risk of tuberculosis infection in Saudi patients receiving adalimumab, etanercept, and tocilizumab therapy.

BACKGROUND: The risk of infection including tuberculosis (TB) infection or reactivation during biological therapy with the current various clinical application is a major concern. This risk may be higher in countries endemic to TB. Our aim of this study is to determine the risk of TB infection in patients receiving 3 biological treatments, Adalimumab, Etanercept and Tocilizumab. METHODS: A retrospective cohort study extending over 2 years follow-up for all patients receiving Adalimumab, Etanercept and Tocilizumab for various clinical indications in a tertiary care center in Saudi Arabia. RESULT: Over the period of 2015-2019, A total of 410 patients received Adalimumab, 271 received Etanercept and 58 patients received Tocilizumab. Rheumatoid arthritis was the most common indication for therapy in all groups and for Adalimumab the most common indication was inflammatory bowel disease, for Etanercept was psoriatic arthritis and for Tocilizumab was juvenile idiopathic arthritis. After a mean follow up period of 36 ± 8.9 months for patients receiving Adalimumab, 21.5 ± 8.4 months for patients receiving Etanercept and 21 ± 2.5 months for patients receiving Tocilizumab there were no reported cases of TB infection in all groups. Only one patient was diagnosed with latent TB 7 months later after starting Adalimumab and tow patients after starting Etanercept. The overall Interferon Gamma Release Assays (IGRA) positivity rate was 9.7%. There was significant association between IGRA positivity rate and patient age. The cutoff age in which IGRA positivity has significantly increased was 53.20 years. CONCLUSION: In our study, patients receiving Etanercept, Adalimumab and Tocilizumab had no increased risk of TB infection. Only 0.3% of patients treated with Adalimumab and 0.9% of patients treated with Etanercept converted to a positive IGRA during therapy.

The safety and efficacy of TNF inhibitors in patients with Behçet's disease: Retrospective study from eastern Turkey.

OBJECTIVE: We aimed to evaluate the clinical features, disease course, and associated factors for outcome in severe/refractory BD patients receiving TNF-i treatment. MATERIAL AND METHODS: This retrospective study was conducted by reviewing medical records from a tertiary referral center in Van province in Eastern Turkey. Data were obtained from patients' charts followed up between June 2019 and June 2022. RESULTS: We included 469 BD patients (59.3% male) whose 80 patients (17%) received TNF-i treatment in the study. The mean ± standard deviation of the patient age was 36.7 ± 10.1 years and the median (IQR) disease duration was 12 (12) years. IFX and ADAwere initiated in 67.5% (n = 54) and 32.5% (n = 26) patients, respectively. Overall and first-line retention rates of TNF-i were 84.7% and 92.6% for IFX and 83.3% and 80.8% for ADA, respectively. IFX was discontinued in 9 patients which were in 2 patients due to allergic reaction and tuberculosis, 3 patients for inefficacy, one patient for heart failure, and one patient for orbital zona. Although no serious adverse event was observed with ADA, 5 patients switched to IFX due to inefficacy. Overall, 72 patients (90%) resumed TNF-i at the end of the study; TNF-i was discontinued in 3 patients (3.8%) due to severe adverse events and in 5 patients (6.2%) with prolonged remission. CONCLUSION: In our study, no case of death was observed in TNF-i receiving patients. Most patients achieved attack-free and CS-free disease and retained TNF-i treatment. TNF inhibitors appear to be safe and effective in patients with severe/refractory Behçet's disease.

Dynamics of serum levels of TNF-α in a longitudinal follow-up study in 98 patients with juvenile idiopathic arthritis treated with anti-TNF-α biological drugs.

OBJECTIVE: To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity. METHODS: We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years. RESULTS: The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores (p = 0.007), (r = - 0.177). CONCLUSION: The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis.

Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial.

BACKGROUND: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. METHODS: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. RESULTS: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. CONCLUSIONS: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. TRIAL REGISTRATION: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .

Loeffler's Endocarditis- A cause of endomyocardial fibrosis in a patient of juvenile idiopathic arthritis: A Case Report.

Endomyocardial fibrosis secondary to hyper-eosinophilic syndrome also known as Loeffler's Endocarditis is a rare cause of restrictive cardiomyopathy. If left untreated, it carries a very high morbidity and mortality rate. The case of a 20 years old girl, a known case of polyarticular juvenile idiopathic arthritis since the age of 13 years was reported at Federal Government Polyclinic Hospital, Islamabad on 14th May 2022. She presented with an acute history of shortness of breath and cough for two weeks. Her initial echocardiogram showed suspicion of Loeffler's Endocarditis, which is attributed to be an adverse effect of etanercept- a tumour necrosis factor (TNF) inhibitor, which she had been prescribed for her arthritis. The patient is currently being managed with high doses of steroids, therapeutic anticoagulation with rivaroxaban, carvedilol for tachycardia and mycophenolate mofetil as an immunosuppressant.

Use of biologics in Chinese pregnant patients with deficiency of interleukin-36 receptor antagonist (DITRA): A case series.

OBJECTIVE: Impetigo herpetiformis (IH) is a rare form of pustular psoriasis which may result in maternal and fetal morbidity and even mortality. Deficiency of interleukin-36 receptor antagonist (DITRA) is the most frequently identified genetic defect of IH. Currently there are no biologics approved for IH despite the revolutionary role of biologics in the treatment of plaque and pustular psoriasis. Anecdotal reports of biologics use in DITRA patients with IH are also limited. CASE REPORTS: We present herein a case series of 6 Chinese IH patients harboring IL36RN gene c.115+6T>C mutation during 8 pregnancies, treated with various biologics, including adalimumab, etanercept and secukinumab. CONCLUSION: Most pregnancy courses were uneventful, except for one woman who had recurrent episodes of decreased fetal heart rate variability after adalimumab injections, which subsided after switching to etanercept. The treatment effectiveness and safety demonstrated in our cases suggested the role of biologics for the treatment of IH in patients with DITRA.

Biologics for Psoriasis.

Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.

Evolving Landscape of Biologic Therapy for Pediatric Psoriasis.

Pediatric psoriasis is a chronic inflammatory skin condition. Current treatment modalities include topical medications, phototherapy, and systemic drugs, including biological agents. In cases of moderate-to-severe psoriasis recalcitrant to other therapies, biological therapies are often an attractive option given their dosing schedules, safety profiles, and need for less frequent laboratory monitoring, when compared with traditional systemic therapies. This article reviews biological treatment options approved for pediatric psoriasis and identifies others actively under investigation.

Additional Data in Expanded Patient Populations and New Indications Support the Practice of Biosimilar-to-Biosimilar Switching.

As of 31 December, 2023, 31 observational studies have been published, including a total of 6081 patients who underwent a switch from one biosimilar to another biosimilar of the same reference biologic. Most studies evaluated infliximab, while a smaller number evaluated adalimumab, rituximab or etanercept. Indications studied now include sarcoidosis, as well as the indications previously reported of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis/ankylosing spondylitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis). This updated data set includes eight additional studies and 2386 more patients compared with those included in an earlier systematic review of biosimilar-to-biosimilar switching. In addition, since the earlier systematic review was published in 2022, the European Medicines Agency has stated that reference-to-biosimilar and biosimilar-to-biosimilar switching in the European Union is safe and efficacy remains unchanged after switching. Furthermore, following a review of the available evidence, the US Food and Drug Administration has confirmed that initial safety and immunogenicity concerns related to biosimilar switching are unfounded and that no differences are observed in efficacy, safety or immunogenicity following one or more switches. The availability of this new efficacy and safety data together with the supportive statements from the European Medicines Agency and the Food and Drug Administration re-confirm the conclusion that as a scientific matter, biosimilar-to-biosimilar switching is an effective clinical practice, with no new safety concerns. Any suggestions to the contrary are not supported by the evidence.

Some Drugs Have Two Faces: Paradoxical Colitis in a Patient with Psoriatic Arthritis Previously Treated with Etanercept and IL-17 Inhibitors.

Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.

Effectiveness and safety of biological and target synthetic drugs treatment for psoriatic arthritis: a systematic review with network meta-analysis.

BACKGROUND: Psoriatic arthritis (PA) is a chronic inflammatory systemic arthritis that can result in loss of functional capacity and joint deformation. This systematic review assessed the effectiveness and safety of biological and target synthetic drugs for treating PA. METHODS: We searched for randomized clinical trials (RCTs) that evaluated the use of Adalimumab, Etanercept, Infliximab, Golimumab, Secukinumab, Certolizumab Pegol and Tofacitinib in the main general databases and clinical trial registers databases. The primary outcomes were ACR 50, PsARC, and serious adverse events. Two independent reviewers performed study selection and data extraction. Network meta-analyses were conducted using a random effects model and frequentist approach. The CINeMA software was used to assess the certainty of evidence. RESULTS: We included 33 RCTs (n = 11,034). The results from the network meta-analysis for the ACR 50 at 6-months follow-up showed that all drugs were superior to placebo, with Secukinumab (high certainty of evidence), Infliximab (very low certainty of evidence) and Adalimumab (high certainty of evidence) ranking the highest. Regarding the PsARC (at 6-months follow-up), all drugs, except for Golimumab (very low certainty of evidence), were superior to placebo, with Etanercept (low certainty of evidence), Infliximab (low certainty of evidence) and Certolizumab Pegol (low certainty of evidence) being the most effective drugs. There were no significant differences in the risk of serious adverse events between the drugs and placebo. Golimumab (very low certainty of evidence), Secukinumab (low certainty of evidence), and Adalimumab (very low certainty of evidence) ranked the highest for safety. CONCLUSIONS: In conclusion, based on the balance between efficacy and safety, Secukinumab and Adalimumab may be the preferred options among the evaluated drugs for treating patients with PsA. However, caution is necessary when interpreting the safety findings, as they are supported by evidence of low to very low certainty. Consequently, the balance between benefits and potential risks may change as new safety evaluation studies become available. PROTOCOL REGISTRATION: PROSPERO: CRD42022315577.

The First Case of a Korean Patient with a Mutation-Confirmed Tumor Necrosis Factor Receptor-Associated Periodic Syndrome.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS, OMIM: #142680) is a rare autoinflammatory disease (AID) with recurrent febrile episodes. To our knowledge, we report herein the first case of a patient with TRAPS in South Korea whose symptoms included fever, arthralgia, abdominal pain, rash, myalgia, cough, and lymphadenopathy. A pathogenic de novo mutation, c.175T>C (p.Cys59Arg), in the tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) gene, was confirmed by gene sequencing. The patient has been with tocilizumab (an interleukin-6 inhibitor); tocilizumab administration every other week has completely alleviated the patient's symptoms. Our report further expands the clinical spectrum of patients with TRAPS and reaffirms the use of tocilizumab as a viable alternative treatment option for those patients who are unsatisfactorily responsive to other commonly used biologics, such as canakinumab, anakinra, infliximab, and etanercept. Furthermore, our report may aid in increasing awareness about the existence of mutation-confirmed TRAPS in South Korea in addition to emphasizing the importance of actively pursuing genetic testing to correctly diagnose rare AID.

Effects of tumor necrosis factor-alpha inhibitors on lipid profiles in patients with psoriasis: a systematic review and meta-analysis.

Background: There is no consensus on the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitors on lipid profiles in patients with psoriasis. This study aimed to investigate the effects of TNF-alpha inhibitors on lipid profiles (triglycerides, total cholesterol, low-density lipoprotein, or high-density lipoprotein) in patients with psoriasis. Methods: We searched PubMed, Embase, and Cochrane Library databases for articles published before October 17, 2023. Four TNF-alpha inhibitors (infliximab, etanercept, adalimumab, and certolizumab) were included in our study. (PROSPERO ID: CRD42023469703). Results: A total of twenty trials were included. Overall results revealed that TNF-alpha inhibitors elevated high-density lipoprotein levels in patients with psoriasis (WMD = 2.31; 95% CI: 0.96, 3.67; P = 0.001), which was supported by the results of sensitivity analyses excluding the effect of lipid-lowering drugs. Subgroup analyses indicated that high-density lipoprotein levels were significantly increased in the less than or equal to 3 months group (WMD = 2.88; 95% CI: 1.37, 4.4; P < 0.001), the etanercept group (WMD = 3.4; 95% CI = 1.71, 5.09, P < 0.001), and the psoriasis group (WMD = 2.52; 95% CI = 0.57, 4.48, P = 0.011). Triglyceride levels were significantly increased in the 3 to 6-month group (WMD = 4.98; 95% CI = 1.97, 7.99, P = 0.001) and significantly decreased in the 6-month and older group (WMD = -19.84; 95% CI = -23.97, -15.7, P < 0.001). Additionally, Triglyceride levels were significantly increased in the psoriasis group (WMD = 5.22; 95% CI = 2.23, 8.21, P = 0.001). Conclusion: Our results revealed that TNF-alpha inhibitors might temporarily increase high-density lipoprotein levels in patients with psoriasis. However, changes in triglycerides were not consistent among the different durations of treatment, with significant increases after 3 to 6 months of treatment. Future prospective trials with long-term follow-up contribute to confirming and extending our findings. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023469703.

Comparative effectiveness of biologics in patients with rheumatoid arthritis stratified by body mass index: a cohort study in a Swiss registry.

OBJECTIVES: Obesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). In patients with obesity, abatacept was suggested as a preferable option to tumour necrosis factor-alpha inhibitors. We aimed to assess the comparative effectiveness of etanercept, infliximab and abatacept, compared with adalimumab, in patients with RA with obesity. Secondarily, we also investigated this in patients with overweight and normal weight for completeness. DESIGN: Observational cohort study. SETTING: Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). PARTICIPANTS: Adult patients with RA from the SCQM registry who received etanercept, infliximab, abatacept or adalimumab as their first biological or targeted synthetic disease-modifying antirheumatic drug were classified based on their body mass index (BMI) at the start of that treatment in three cohorts: obese, overweight, normal weight. They were followed for a maximum of 1 year. EXPOSURE: The study exposure of interest was the patients' first biological, particularly: etanercept, infliximab and abatacept, compared with adalimumab. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study outcome was remission within 12 months, defined as 28-joint Disease Activity Score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction. Logistic regression was used to compare the effectiveness of etanercept, infliximab and abatacept versus adalimumab. Each BMI cohort was addressed and analysed separately. RESULTS: The study included 443 obese, 829 overweight and 1243 normal weight patients with RA. There were no statistically significant differences in the odds of DAS28-remission at ≤12 months for etanercept, infliximab and abatacept, compared with adalimumab, in any of the BMI cohorts. CONCLUSIONS: No differences in DAS28-remission were found between the study drugs and adalimumab as first biologic in patients with RA, independently of the BMI cohort. We did not find evidence that treatment with abatacept increased the likelihood of remission compared with adalimumab among obese patients with RA.

Peri-Transplant Inflammation and Long-Term Diabetes Outcomes Were Not Impacted by Either Etanercept or Alpha-1-Antitrypsin Treatment in Islet Autotransplant Recipients.

The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3 months post-TPIAT. Here, we report 2-year diabetes outcomes and peri-operative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucose-potentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period.

Exploring the influence of baseline rheumatoid factor levels on TNF inhibitor retention rate in patients with rheumatoid arthritis: a multicentre and retrospective study.

OBJECTIVE: To assess whether the retention rate of certolizumab pegol (CZP) was longer than that of other tumour necrosis factor inhibitors (TNFi) based on baseline rheumatoid factor (RF) levels. METHODS: Longitudinal, retrospective and multicentre study including patients with RA who were treated with any TNFi (monoclonal antibodies (mAB), etanercept (ETA) or CZP). Log-rank test and Cox regressions were conducted to evaluate the retention rate in the three groups according to the level of RF, with the third quartile of the baseline levels used as cut-off: <200 (

Prediction of ineffectiveness of biological drugs using machine learning and explainable AI methods: data from the Austrian Biological Registry BioReg.

OBJECTIVES: Machine learning models can support an individualized approach in the choice of bDMARDs. We developed prediction models for 5 different bDMARDs using machine learning methods based on patient data derived from the Austrian Biologics Registry (BioReg). METHODS: Data from 1397 patients and 19 variables with at least 100 treat-to-target (t2t) courses per drug were derived from the BioReg biologics registry. Different machine learning algorithms were trained to predict the risk of ineffectiveness for each bDMARD within the first 26 weeks. Cross-validation and hyperparameter optimization were applied to generate the best models. Model quality was assessed by area under the receiver operating characteristic (AUROC). Using explainable AI (XAI), risk-reducing and risk-increasing factors were extracted. RESULTS: The best models per drug achieved an AUROC score of the following: abatacept, 0.66 (95% CI, 0.54-0.78); adalimumab, 0.70 (95% CI, 0.68-0.74); certolizumab, 0.84 (95% CI, 0.79-0.89); etanercept, 0.68 (95% CI, 0.55-0.87); tocilizumab, 0.72 (95% CI, 0.69-0.77). The most risk-increasing variables were visual analytic scores (VAS) for abatacept and etanercept and co-therapy with glucocorticoids for adalimumab. Dosage was the most important variable for certolizumab and associated with a lower risk of non-response. Some variables, such as gender and rheumatoid factor (RF), showed opposite impacts depending on the bDMARD. CONCLUSION: Ineffectiveness of biological drugs could be predicted with promising accuracy. Interestingly, individual parameters were found to be associated with drug responses in different directions, indicating highly complex interactions. Machine learning can be of help in the decision-process by disentangling these relations.

Patient self-reported experience and satisfaction with golimumab and etanercept treatments for rheumatic diseases: A cohort study.

Golimumab and etanercept both exhibit good efficacy in treating rheumatic diseases, while the patient self-reported measurement of treatment improvement and injection experience lacks sufficient evidence. Hence, this study aimed to compare the satisfaction with disease improvement and injection experience and the level of injection site reactions (ISRs) between golimumab-treated and etanercept-treated patients with rheumatic diseases. A total of 312 patients with rheumatic diseases were serially enrolled. Among them, 158 patients received golimumab (golimumab group); the other 154 patients were treated with etanercept (etanercept group) according to the actual disease status, physician advice, and patient willingness. Satisfaction with disease improvement was assessed using the 7-point Likert scale; satisfaction with injection experience and level of ISRs were both determined by the 5-point Likert scale. Satisfaction degrees with global injection experience (P = .025), injection device (P = .008), injection frequency (P = .010), and injection convenience (P = .003) were superior in the golimumab group to the etanercept group, while satisfaction degrees with global disease improvement, symptom relief, and speed of action did not vary (all P > .050) between the 2 groups. Discomfort (P = .005), swelling (P < .001), pain (P = .028), and burning (P = .035) levels were lower in the golimumab group than in the etanercept group. In addition, among 56 patients with a history of tumor necrosis factor inhibitor treatment before golimumab, 40 (71.4%) patients preferred golimumab to other tumor necrosis factor inhibitor. After switching to golimumab treatment, the level of ISRs in most patients was reduced or comparable. Golimumab achieves a satisfying injection experience and relieves the level of ISRs over etanercept in patients with rheumatic diseases.

Use of Efficiency Frontiers to Align Prices and Clinical Benefits of Biologic Therapies for Plaque Psoriasis.

Importance: The US lacks a systematic approach for aligning drug prices with clinical benefit, and traditional cost-effectiveness analysis (CEA) faces political obstacles. The efficiency frontier (EF) method offers policymakers an alternative approach. Objective: To assess how the EF approach could align prices and clinical benefits of biologic medications for plaque psoriasis and estimate price reductions in the US vs 4 peer countries: Australia, Canada, France, and Germany. Design and Setting: This health economic evaluation used the EF approach to compare the prices and clinical benefits of 11 biologics and 2 biosimilars for plaque psoriasis in the US, Australia, Canada, France, and Germany. Data were collected from February to March 2023 and analyzed from March to June 2023. Main Outcome Measures: EFs were constructed based on each biologic's efficacy, measured using the Psoriasis Area and Severity Index (PASI) 90 response rate, and annual treatment cost as of January 2023; US costs were net of estimated manufacturer rebates. Prices based on the EF were compared with traditional CEA-based prices calculated by the Institute for Clinical and Economic Review at a threshold of $150 000 per quality-adjusted life-year gained. Results: Among 13 biologics, PASI 90 response rates ranged from 17.9% (etanercept) to 71.6% (risankizumab); US net annual treatment costs ranged from $1664 (infliximab-dyyb) to $79 277 (risankizumab). The median (IQR) net annual treatment cost was higher in the US ($34 965 [$20 493-$48 942]) than prerebate costs in Australia ($9179 [$6691-$12 688]), Canada ($15 556 [$13 017-$16 112]), France ($9478 [$6637-$11 678]), and Germany ($13 829 [$13 231-$15 837]). The US EF included infliximab-dyyb (PASI 90: 57.4%; annual cost: $1664), ixekizumab (PASI 90: 70.8%; annual cost: $33 004), and risankizumab (PASI 90: 71.6%; annual cost: $79 277). US prices for psoriasis biologics would need to be reduced by a median (IQR) of 71% (31%-95%) to align with those estimated using the EF; the same approach would yield smaller price reductions in Canada (41% [6%-57%]), Australia (36% [0%-65%]), France (19% [0%-67%]), and Germany (11% [8%-26%]). Except for risankizumab, the EF-based prices were lower than the prices based on traditional CEA. Conclusions and Relevance: This economic evaluation showed that for plaque psoriasis biologics, using an EF approach to negotiate prices could lead to substantial price reductions and better align prices with clinical benefits. US policymakers might consider using EFs to achieve prices commensurate with comparative clinical benefits, particularly for drug classes with multiple therapeutic alternatives for which differences can be adequately summarized by a single outcome measurement.