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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 -
ACS Chemical Biology Jun 2024Eliminating the core fucose from the -glycans of the Fc antibody segment by pathway engineering or enzymatic methods has been shown to enhance the potency of therapeutic...
Eliminating the core fucose from the -glycans of the Fc antibody segment by pathway engineering or enzymatic methods has been shown to enhance the potency of therapeutic antibodies, especially in the context of antibody-dependent cytotoxicity (ADCC). However, there is a significant challenge due to the limited defucosylation efficiency of commercially available α-l-fucosidases. In this study, we report a unique α-l-fucosidase (fucA) from the bacterium that has a low sequence identity compared with all other known α-l-fucosidases and is highly reactive toward a core disaccharide substrate with fucose α(1,3)-, α (1,4)-and α(1,6)-linked to GlcNAc, and is less reactive toward the Fuc-α(1,2)-Gal on the terminal trisaccharide of the oligosaccharide Globo H (Bb3). The kinetic properties of the enzyme, such as its and , were determined and the optimized expression of fucA gave a yield exceeding 30 mg/L. The recombinant enzyme retained its full activity even after being incubated for 6 h at 37 °C. Moreover, it retained 92 and 87% of its activity after freezing and freeze-drying treatments, respectively, for over 28 days. In a representative glycoengineering of adalimumab (Humira), fucA showed remarkable hydrolytic efficiency in cleaving the α(1,6)-linked core fucose from FucGlcNAc on the antibody with a quantitative yield. This enabled the seamless incorporation of biantennary sialylglycans by Endo-S2 D184 M in a one-pot fashion to yield adalimumab in a homogeneous afucosylated glycoform with an improved binding affinity toward Fcγ receptor IIIa.
PubMed: 38912881
DOI: 10.1021/acschembio.4c00196 -
Dermatology and Therapy Jun 2024Hidradenitis suppurativa (HS) is a frequently debilitating, inflammatory skin condition. Patients may have a limited response to adalimumab, currently the only Food and...
INTRODUCTION
Hidradenitis suppurativa (HS) is a frequently debilitating, inflammatory skin condition. Patients may have a limited response to adalimumab, currently the only Food and Drug Administration (FDA)-approved biologic treatment for HS. Ustekinumab is an interleukin-12/23 inhibitor that has been utilized in HS, but there is a lack of an updated systematic review on its efficacy and safety. The aim of this study is to perform a systematic review and meta-analysis of the literature on the efficacy and safety of ustekinumab for HS.
METHODS
In October 2022, MEDLINE and Embase databases were searched for articles on ustekinumab in HS. Data extraction was performed on relevant articles by two reviewers. The primary study outcome was the pooled response rate of HS to ustekinumab. A fixed-effects meta-analysis was performed, and Cochran's Q statistic and I squared index were used to assess heterogeneity. Statistical significance was determined at p < 0.05. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
RESULTS
From 2012 to 2022, ten articles (nine case series and one prospective trial) with 88 patients met the inclusion criteria. Patients with reported disease severity had Hurley stage II (17.6%, 12/68) or III (82.4%, 56/68) disease. The majority (80.7%, 71/88) had previously failed at least one biologic treatment. A meta-analysis of all ten studies showed a pooled response rate of 67% (95% CI 0.57-0.76). Study limitations include a small number of patients and randomized controlled trials (RCTs).
CONCLUSIONS
Ustekinumab may be a helpful treatment option to consider for HS that is recalcitrant to first-line biologic therapies, but RCTs are needed to determine optimal dosing regimens and the specific patient populations that would benefit the most from this agent.
PubMed: 38907878
DOI: 10.1007/s13555-024-01207-y -
European Journal of Dermatology : EJD Apr 2024
Topics: Humans; Psoriasis; Male; Female; Republic of Korea; Aged; Middle Aged; Treatment Outcome; Adalimumab; Retrospective Studies; Antibodies, Monoclonal, Humanized; Age Factors; Etanercept; Infliximab; Severity of Illness Index
PubMed: 38907558
DOI: 10.1684/ejd.2024.4644