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Pharmaceutics May 2024Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient's circulating drug levels. Using modelling and...
Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient's circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.
PubMed: 38931826
DOI: 10.3390/pharmaceutics16060702 -
Biomolecular NMR Assignments Jun 2024Adalimumab is a therapeutic monoclonal antibody developed to target human TNF an important mediator of immune-mediated inflammatory diseases such as rheumatoid...
Adalimumab is a therapeutic monoclonal antibody developed to target human TNF an important mediator of immune-mediated inflammatory diseases such as rheumatoid arthritis, amongst others. The 48 kDa Fab fragment of adalimumab was produced in Escherichia coli using a single chain approach to allow complete isotopic incorporation of deuterium, carbon-13 and nitrogen-15 along with the protonated isoleucine-d, valine and leucine methyl groups. Here we report the near complete resonance assignment of the polypeptide backbone and the methyl groups of isoleucine, leucine and valine residues.
PubMed: 38926254
DOI: 10.1007/s12104-024-10187-1 -
European Journal of Hospital Pharmacy :... Jun 2024In the Danish healthcare system, restructuring is an ongoing process to accommodate the rising number of patients and to optimise resource allocation. To ease...
OBJECTIVES
In the Danish healthcare system, restructuring is an ongoing process to accommodate the rising number of patients and to optimise resource allocation. To ease departmental burdens at hospitals in the North Denmark Region, outpatients are empowered to collect their cost-free medicines from medication pick-up lockers. The lockers function similarly to a package box, thereby enhancing patient freedom. Due to lack of evidence within the published literature regarding cost-free medicines and medicine waste, the aim of our study was to identify the common medications delivered to medicine pick-up lockers and secondly, to evaluate potential medicine waste.
METHODS
Data from ApoVision provided insights into medications delivered to medicine pick-up lockers from March to October 2023 in the North Denmark Region. To estimate unused medicines we obtained data on the number of medications returned from medicine pick-up lockers.
RESULTS
From 2020 to 2023, the number of patients receiving cost-free medicines at medication pick-up lockers increased. In total, approximately 30 000 packages of medicine were delivered to medicine pick-up lockers from March to October 2023 in the North Denmark Region; 1.7% were returned. Methotrexate, adalimumab, and omalizumab were among the most common deliveries and were also the three most returned from the medicine pick-up lockers.
CONCLUSIONS
This study is an initial attempt to investigate potential medicine waste in cost-free medicines dispensed to outpatients via pick-up lockers. Antineoplastic and immunomodulating agents were the most common medicines delivered to medication pick-up lockers in the North Denmark Region from March to October 2023. In this period, approximately 2% of all delivered medicine packages were returned to the hospital pharmacy. Our analysis solely focuses on waste associated with medications left uncollected from medicine pick-up lockers. Addressing the impact of medicine waste in a hospital setting requires a comprehensive approach, thus future studies should also focus on other sites relevant for medication waste as, for example, the patient's household.
PubMed: 38925908
DOI: 10.1136/ejhpharm-2024-004224 -
Blood Advances Jun 2024Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cell (HSC) advantage and contributing to a phenomenon termed...
Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cell (HSC) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing TNF favours TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2-mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- genotypes reconstituted with WT CD45.1+ and Tet2-/-CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2-/-cells in old WT recipient mice, with strong skewing towards the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- recipient mice, suggesting that TNF signalling is essential for the expansion Tet2-mutant myeloid clones. Examination of human rheumatoid arthritis patients with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.
PubMed: 38924753
DOI: 10.1182/bloodadvances.2023011833 -
The Australasian Journal of Dermatology Jun 2024Caucasian and Asian patients with hidradenitis suppurativa demonstrate significant differences with regard to age, gender and body mass index. Demographic...
Response to adalimumab in Caucasian and Asian patients with hidradenitis suppurativa: A retrospective cohort study of an Australian cohort stratified by patient-reported ethnicity.
BACKGROUND/OBJECTIVES
Caucasian and Asian patients with hidradenitis suppurativa demonstrate significant differences with regard to age, gender and body mass index. Demographic characteristics are known to influence the efficacy and drug survival of hidradenitis suppurativa therapeutics including biologic therapies. What remains unknown is the impact of ethnicity upon the efficacy of therapeutics once demographic and disease characteristics have been taken into account. This is an important question given the expansion of biologic therapies for HS into the global patient community.
METHODS
We assessed 170 patients from a single HS specialist centre in Australia stratified by patient-identified ethnicity including those identifying as either Caucasian or Asian.
RESULTS
Asian patients demonstrated lower BMI, higher rates of smoking and greater odds of Hurley stage 3 disease with tunnels than Caucasian patients in line with the reported literature. There was no significant difference between percentage of individuals achieving HiSCR50 or IHS4-55 at Week 16. Significant differences were seen in median time to secondary loss of response, and Kaplan-Meier curve analysis showed a significant difference between curves when stratified by patient-reported ethnicity. Cox regression analysis demonstrated after accounting for age, gender, BMI, smoking and Hurley stage, the significance of ethnicity in influencing time to secondary loss of response disappears.
CONCLUSIONS
Caucasian or Asian ethnicity does not influence response to adalimumab treatment on patients with hidradenitis suppurativa.
PubMed: 38924541
DOI: 10.1111/ajd.14343 -
JAMA Network Open Jun 2024Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying... (Comparative Study)
Comparative Study
IMPORTANCE
Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying antirheumatic drugs (DMARDs) provides better clinical efficacy compared with conventional synthetic DMARDs recommended by current treatment guidelines; but its cost-effectiveness evidence remains unclear.
OBJECTIVE
To evaluate the cost-effectiveness of the treatment sequence initiated with biosimilar DMARDs after failure with methotrexate vs leflunomide and inform formulary listing decisions.
DESIGN, SETTING, AND PARTICIPANTS
This economic evaluation's cost-effectiveness analysis was performed at a Hong Kong public institution using the Markov disease transition model to simulate the lifetime disease progression and cost for patients with RA, using monetary value in 2022. Scenario and sensitivity analyses were performed to test the internal validity of the modeling conclusion. Participants included patients diagnosed with RA from 2000 to 2021 who were retrieved retrospectively from local electronic medical records to generate model input parameters. Statistical analysis was performed from January 2023 to March 2024.
INTERVENTIONS
The model assesses 3 competing treatment sequences initiated with biosimilar infliximab (CT-P13), biosimilar adalimumab (ABP-501), and leflunomide; all used in combination with methotrexate.
MAIN OUTCOMES AND MEASURES
Lifetime health care cost and quality-adjusted life-years (QALYs) of the simulated cohort.
RESULTS
In total, 25 099 patients with RA were identified (mean [SD] age, 56 [17] years; 19 469 [72.7%] women). In the base-case analysis, the lifetime health care cost and QALYs for the treatment sequence initiated with leflunomide were US $154 632 and 14.82 QALYs, respectively; for biosimilar infliximab, they were US $152 326 and 15.35 QALYs, respectively; and for biosimilar adalimumab, they were US $145 419 and 15.55 QALYs, respectively. Both biosimilar sequences presented lower costs and greater QALYs than the leflunomide sequence. In the deterministic sensitivity analysis, the incremental cost-effectiveness ratio (US$/QALY) comparing biosimilar infliximab sequence vs leflunomide sequence and biosimilar adalimumab sequence vs leflunomide sequence ranged from -15 797 to -8615 and -9088 to 10 238, respectively, all below the predefined willingness-to-pay threshold (US $48 555/QALY gain). In the probabilistic sensitivity analysis, the probability of treatment sequence initiated with leflunomide, biosimilar infliximab, and biosmilar adalimumab being cost-effective out of 10 000 iterations was 0%, 9%, and 91%, respectively.
CONCLUSIONS AND RELEVANCE
In this economic evaluation study, the treatment sequences initiated with biosimilar DMARDs were cost-effective compared with the treatment sequence initiated with leflunomide in managing patients with RA who experienced failure with the initial methotrexate treatment. These results suggest the need to update clinical treatment guidelines for initiating biosimilars immediately after the failure of methotrexate for patients with RA.
Topics: Humans; Arthritis, Rheumatoid; Leflunomide; Biosimilar Pharmaceuticals; Cost-Benefit Analysis; Antirheumatic Agents; Female; Male; Middle Aged; Infliximab; Adult; Hong Kong; Retrospective Studies; Quality-Adjusted Life Years; Adalimumab; Aged
PubMed: 38922614
DOI: 10.1001/jamanetworkopen.2024.18800 -
JAMA Dermatology Jun 2024
PubMed: 38922593
DOI: 10.1001/jamadermatol.2024.1775 -
Zeitschrift Fur Gastroenterologie Jun 2024As of now, there exists no established therapy for ELP. Retinoids, which are standard in treating cutaneous LP, do not exhibit positive effects in ELP. While topical...
As of now, there exists no established therapy for ELP. Retinoids, which are standard in treating cutaneous LP, do not exhibit positive effects in ELP. While topical glucocorticosteroids often yield favorable responses in esophageal inflammation, some cases prove recalcitrant or refractory. In such instances, various immunosuppressive therapies have been attempted with variable success.This report details a severe case of ELP that showed resistance to prednisolone, acitretin, alitretinoin, adalimumab, tacrolimus, hydroxychloroquine plus mycophenolate mofetil, and cyclophosphamide. The initiation of the JAK inhibitor tofacitinib induced an impressive clinical, endoscopic, and histological remission. This positive response to a JAK inhibitor is discussed in the context of our evolving understanding of the immune-mediated pathogenesis of this disease.
PubMed: 38917831
DOI: 10.1055/a-2300-0375 -
Ocular Immunology and Inflammation Jun 2024Uveitis is a common ocular manifestation in individuals with sarcoidosis, a multisystem inflammatory disorder. This study aimed to explore clinical and genetic factors...
PURPOSE
Uveitis is a common ocular manifestation in individuals with sarcoidosis, a multisystem inflammatory disorder. This study aimed to explore clinical and genetic factors associated with the presence or absence of uveitis in sarcoidosis patients.
METHODS
Total 625 Dutch sarcoidosis patients were included. Among these, 170 underwent ophthalmic examination, and 61 were diagnosed with uveitis. Demographic and clinical data, including age, gender, race, biopsy status, chest radiography findings, TNF-α inhibitor treatment, and uveitis classification were collected retrospectively from medical records. Genetic data was available for HLA haplotypes, G-308A, and G16071A polymorphisms.
RESULTS
The majority of the patients presented with bilateral uveitis (80.3%). The proportion of women was higher in the uveitis group compared to the non-uveitis group (67.2% and 47.7%; = 0.014). Pulmonary involvement (chest radiographic stage II-III) was significantly lower in patients with uveitis (36.1% versus 64.2%; < 0.001). Patients with uveitis were more often treated with TNF-α inhibitors (67.2% versus 29.4%; < 0.001) and the outcome was better compared with the non-uveitis group, 92% vs 68%, responders ( < 0.012). Uveitis patients treated with TNF-α inhibitors (either adalimumab or infliximab) were more likely to suffer from intermediate or posterior uveitis than anterior uveitis. Genetic analysis identified a significant association between the G16071A GG genotype and uveitis ( = 0.012).
CONCLUSION
This study highlights distinctive demographic, clinical and genetic features associated with uveitis in sarcoidosis patients. Ocular sarcoidosis was more prevalent in women. Further research is warranted to explore the implications of these findings for treatment strategies and prognostic assessments.
PubMed: 38916581
DOI: 10.1080/09273948.2024.2369931 -
International Journal of Clinical... Jun 2024Treatment of arthritis is carried out using corticosteroids, methotrexate, sulfasalazine-like agents, and TNF-α-blocking agents such as infliximab and adalimumab. The...
BACKGROUND
Treatment of arthritis is carried out using corticosteroids, methotrexate, sulfasalazine-like agents, and TNF-α-blocking agents such as infliximab and adalimumab. The disadvantages of these agents are high-cost, severe side effects including leucopenia, and in some cases the necessity of administration by injection. Polyvalent immunoglobulin formulations derived from bovine colostrum and marketed as a standardized formulation for oral application, are reported to be efficacious in chronic pain syndromes but are rarely, if ever, used as an alternative medication in such patients.
AIMS
To treat arthritis in a real-world setting using polyvalent immunoglobulins in 2 patients, in one case where no alternative treatment modality was available and in another patient in whom the use of polyvalent immunoglobulins appeared to be a suitable option.
MATERIALS AND METHODS
Two male subjects aged 46 and 82 years with confirmed diagnosis but not well-controlled arthritis/polyarthritis receiving either high-dose NSAIDS, corticosteroids, methotrexate injections, with previous use of, or recommendations for treatment with monoclonal antibodies (etanercept and adalimumab) were treated with oral polyvalent immunoglobulins (KMP01; dose range 10 - 20 g daily) in real-world settings, in one case during a field excursion in Peru.
RESULTS
The treatment produced a rapid alleviation of pain in both patients, in one patient where the symptoms were severe and debilitating. In the second patient methotrexate SC injections could be discontinued, and there was a progressive reversal of leucopenia (leucocyte count 3.9 × 10/µL) over a period of ~ 3 months.
DISCUSSION
Polyvalent immunoglobulins have been shown previously to reduce the expression of interleukin-6 and C-reactive protein in peripheral blood monocytes, events attributed to the neutralization of gut-derived endotoxin ligands lipopolysaccharides (LPS) driving the basal immune response. The mode of action of KMP01 on cytokine expression is therefore similar to the TNF-α-blocking agents etanercept and adalimumab.
CONCLUSION
Findings from two case reports support the rationale for using polyvalent immunoglobulins as an effective and safe alternative in arthritis patients receiving standard treatments, in particular, methotrexate and TNF-α-blocking agents.
PubMed: 38916486
DOI: 10.5414/CP204615