Revolutionizing Ophthalmic Care: A Review of Ocular Hydrogels from Pathologies to Therapeutic Applications.

PURPOSE: This comprehensive review is designed to elucidate the transformative role and multifaceted applications of ocular hydrogels in contemporary ophthalmic therapeutic strategies, with a particular emphasis on their capability to revolutionize drug delivery mechanisms and optimize patient outcomes. METHODS: A systematic and structured methodology is employed, initiating with a succinct exploration of prevalent ocular pathologies and delineating the corresponding therapeutic agents. This serves as a precursor for an extensive examination of the diverse methodologies and fabrication techniques integral to the design, development, and application of hydrogels specifically tailored for ophthalmic pharmaceutical delivery. The review further scrutinizes the pivotal manufacturing processes that significantly influence hydrogel efficacy and delves into an analysis of the current spectrum of hydrogel-centric ocular formulations. RESULTS: The review yields illuminating insights into the escalating prominence of ocular hydrogels within the medical community, substantiated by a plethora of ongoing clinical investigations. It reveals the dynamic and perpetually evolving nature of hydrogel research and underscores the extensive applicability and intricate progression of transposing biologics-loaded hydrogels from theoretical frameworks to practical clinical applications. CONCLUSIONS: This review accentuates the immense potential and promising future of ocular hydrogels in the realm of ophthalmic care. It not only serves as a comprehensive guide but also as a catalyst for recognizing the transformative potential of hydrogels in augmenting drug delivery mechanisms and enhancing patient outcomes. Furthermore, it draws attention to the inherent challenges and considerations that necessitate careful navigation by researchers and clinicians in this progressive field.

Vaccination strategies for patients under monoclonal antibody and other biological treatments: an updated comprehensive review based on EMA authorizations to January 2024.

INTRODUCTION: Monoclonal antibodies (mAbs) and other biological agents are being increasingly approved in the last years with very different indications. Their highly heterogeneous immunosuppressive effects, mechanisms of action and pharmacokinetics require comprehensive individualized vaccination schedules. AREAS COVERED: Vaccination for immunocompromised patients. Prevention and treatment with mAbs and other biological therapies. EXPERT OPINION: Current recommendations on vaccine schedules for patients under mAbs or other biological treatments are based on expert opinions and are not individualized according to each vaccine and treatment. No studies are focusing on the high heterogeneity of these agents, that are exponentially developed and used for many different indications. Recent paradigm changes in vaccine development (boosted by the COVID-19 pandemic) and in the mAbs use for prophylactic purposes (changing 'vaccination' by 'immunization' schedules) has been witnessed in the last years. We aimed at collecting all mAbs used for treatment or prevention, approved as of 1 January 2024, by the EMA. Based on available data on mAbs and vaccines, we propose a comprehensive guide for personalizing vaccination. Recent vaccine developments and current population strategies (e.g. zoster vaccination or prophylactic nirsevimab) are discussed. This review aims to be a practical guideline for professionals working in vaccine consultations for immunosuppressed patients.

The new biologic drugs: Which children with asthma should get what?

Novel biologics (targeted antibody therapies) have revolutionized the management of severe childhood asthma. However, it is important that the right biologic is selected for the right patient, and understanding the evidence base for each biologic is crucial. Currently, four biologics (all monoclonal antibodies) are licensed in the UK for the treatment of children with severe asthma - omalizumab (Xolair), mepolizumab (Nucala), and dupilumab (Dupixent) in children aged 6 years and over; and tezepelumab (Tezspire), only in children aged 12 years and over. Tezepelumab is the only licensed biological that may be beneficial in severe asthma without evidence of Type 2 inflammation. All have a good safety profile but varying degrees of clinical efficacy in children, with wide variation in treatment responsiveness between individual patients. When selecting biologics for severe asthma, it is essential to remember the limitations of the current pediatric evidence. At present, there are no results from randomized, head-to-head trials of biologics in severe asthma. TREAT is an ongoing trial comparing omalizumab to mepolizumab and will be one of the first to provide such evidence. We must be especially aware of the dangers of extrapolating data from adults to children, because the pathophysiology and role of biomarkers may differ significantly from adult asthma. Given the current level of knowledge, even after treatment has been initiated, children should be regularly reviewed to determine the efficacy of treatment, side-effect profile and consideration of when treatment with the biologic should be discontinued.

A review of biosimilars in psoriasis: impacts on efficacy, safety, access, and a first-hand look at biosimilar cost savings within the department of veterans affairs.

BACKGROUND: Psoriasis is a chronic immune-mediated systemic disease whose treatment has been revolutionized due to the induction of monoclonal antibody-based biologics. However, access to these drugs has been limited due to their high cost. Biosimilars utilize reverse engineering to create a highly similar product to an originator drug following patent expiration and provide an avenue to reduce costs of biologic treatment. This review seeks to synthesize current knowledge about the development, efficacy, and established benefits of biosimilars, including cost savings and increased access to biologic medicines. RESULTS: In 2023, the Veterans Health Administration (VA) generated a cost avoidance of over 67 million dollars through use of 6 currently adopted biosimilars across all indications. There is an opportunity for further cost avoidance, with the pre-set percent discount of statutory contract prices necessary for the adoption of future biosimilars, including adalimumab and etanercept, set at over 50%. CONCLUSIONS: Biosimilars appear to offer an overall effective, safe, and well-tolerated treatment method for patients with psoriasis and are already providing substantial cost savings within the VA. Additional education is needed to address sources of ambivalence for both patients and providers to assist in further uptake of biosimilars for the treatment of psoriasis.

Use of Stable Isotope Labeled (SIL) Antibodies in Cassette Dosing to Improve Pharmacokinetics Screening Efficiency of ADCs with Novel Cytotoxic Payloads.

Stable isotope labeling by amino acids in cell culture (SILAC) is an established technique used in quantitative mass spectrometry (MS)-based proteomics. SILAC is also used to generate stable isotope labeled (SIL) antibodies for internal standards (IS) used in LC-MS/MS bioassays to improve quantitative robustness.Total antibody (TAb) is measured to evaluate pharmacokinetic (PK) of antibody drug conjugate (ADC) candidates measured by either ligand binding (LBA) or LC-MS/MS. Herein, we describe an application of SILAC, where multiple SIL combinations of an antibody are used for cassette dosing and PK evaluation.Our preclinical studies demonstrate SILAC-labeled ADC therapeutics did not alter antibody PK. Furthermore, with cassette dosing SIL antibodies exhibited comparable exposure to discretely administered unlabeled test articles in rats.In addition, SIL antibodies were conjugated to cytotoxic payloads to create SIL ADCs and cassette dosed in a cynomolgus monkey PK study and SIL ADCs yielded comparable PK results to discrete dosed unlabeled ADCs.In conclusion, SIL antibodies used with a cassette dosing strategy increases PK screening throughput of ADC candidates in preclinical species. Additionally, cassette dosing strategy further facilitates the responsible use of laboratory animals to achieve the three-Rs (Replacement, Reduction, and Refinement).

Current Pharmacologic Options and Emerging Therapeutic Approaches for the Management of Ulcerative Colitis: A Narrative Review.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory bowel disorder (IBD) with periods of relapse and remission. Current advancements in clinical research have led to the development of more refined and effective medical therapy for UC. Summary of the Evidence: Traditional therapeutic agents such as 5-aminosalicylates (5-ASAs), sulfasalazine (SASP), corticosteroids, and immunomodulatory drugs have remained the gold standard for decades. However, their novel formulations and dosage regimens have changed their sequences in the medical management of UC. Several other novel drugs are in the final phases of clinical development or have recently received regulatory approval designed to target specific mechanisms involved in the inflammatory cascade for UC. Conclusions: This narrative review sought to provide a comprehensive knowledge of the potential benefits of standard and emerging therapies, including novel formulations, new chemical entities, and novel therapeutic approaches in managing UC. Keywords: Ulcerative colitis, 5- Aminosalicylic acid, sulfasalazine, corticosteroids, biologics, immunomodulators, novel formulations.

Uncovering the Differences: How DLQI and WHO-5 Scores Vary in Moderate-to-Severe Psoriasis Patients Treated with Tildrakizumab 100 mg vs. 200 mg?

Background/Objectives: Psoriasis (PsO) is a chronic inflammatory skin disease that severely impacts patients' quality of life (QoL). Its global prevalence is about 2%, with significant regional variations. PsO manifests in the form of erythematous and scaly plaques, causing intense pruritus and discomfort and limiting daily activities. The condition often includes comorbidities such as psoriatic arthritis, cardiovascular diseases, and metabolic syndrome, further deteriorating QoL. Psychological well-being is notably affected, with high levels of depression and anxiety due to the visible lesions, leading to social stigma and isolation. QoL indexes like WHO-QoL and SF-36 assess various well-being aspects, while patient-reported outcomes (PROs) provide a comprehensive understanding of PsO's impact. However, there are no universally shared PROs in outpatient practice to fully understand the impact of the disease and associated therapies. This study aims to evaluate differences between DLQI and WHO-5 in adult patients with moderate-to-severe PsO treated with tildrakizumab 100 mg or 200 mg. Methods: The study was conducted at the University Hospital of Siena, Italy, from May 2023 to April 2024. Data from 15 patients treated with tildrakizumab 200 mg and 15 patients treated with tildrakizumab 100 mg, observed for at least 28 weeks, were recorded. Demographic data, PASI, DLQI, and WHO-5 scores were analyzed. Patients in the 100 mg group (G100) were selected to match the demographic characteristics of the 200 mg group (G200). Reduction rates of DLQI and WHO-5 were assessed at baseline values and after 4, 16, and 28 weeks. Results: Both groups experienced improvements in QoL. The group treated with 200 mg showed more pronounced and rapid reductions in DLQI and WHO-5 scores compared to the 100 mg group. WHO-5 demonstrated faster improvements in overall well-being than DLQI, indicating its greater sensitivity to changes in mental well-being and overall QoL. No differences in adverse events were observed between the two groups, with no major adverse events reported. Conclusions: In our study, WHO-5 proved more sensitive than DLQI in capturing well-being changes in PsO patients treated with tildrakizumab. However, a combined use of both WHO-5 and DLQI questionnaires should be encouraged in clinical practice. Furthermore, this study confirmed the superior QoL improvement associated with tildrakizumab 200 mg compared to 100 mg. Future research should explore the long-term impact on QoL and comparative effectiveness among other biologic therapies in diverse patient populations.

Increased risk of Pneumocystis jirovecii colonization in rheumatoid arthritis patients on biologics and Janus kinase inhibitor.

BACKGROUND: The prevalence of Pneumocystis jirovecii (PJ) pneumonia among rheumatic patients is rising. PJ colonization serves as a reservoir for transmission and precedes the development of PJ pneumonia. We aim to clarify the association of PJ colonization in patients of rheumatoid arthritis (RA) treated with biologics or Janus kinase inhibitors (JAKi). METHODS: A prospective cohort study was performed from March 2021 to July 2022 in the rheumatology outpatient department of National Cheng Kung University Hospital. We obtained oral-wash samples from asymptomatic RA patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and JAKi. A real-time quantitative polymerase chain reaction assay focusing on the mitochondrial large subunit ribosomal ribonucleic acid gene of PJ was applied to detect colonization. RESULTS: One hundred and ten RA patients were enrolled. Adjusted odds ratios (ORs) of PJ colonization were 6.40 (95% CI 1.34-30.57, p-value =0.02) in patients receiving bDMARDs or JAKi. Specifically, in patients treated with bDMARDs the adjusted OR was 8.08 (95% CI 1.57-41.51, p-value=0.012), and a trend toward developing PJ colonization was further identified in patients receiving JAKi (adjusted OR: 4.79, 95% CI 0.89-25.91, p=0.069). Among patients treated with bDMARDs or JAKi, medication duration >3 years and age >60 y/o are risk factors for PJ colonization. CONCLUSION: RA patients on bDMARDs or JAK inhibitors have an approximately 6-fold higher risk of developing P. jirovecii colonization. Patients treated with bDMARDs had an 8-fold higher risk of P. jirovecii colonization. Risk factors of PJ colonization are medication duration >3 years and age > 60 y/o.

Biologics for eosinophilic otitis media: a retrospective case study in a multidisciplinary center.

PURPOSE: Eosinophilic otitis media (EOM) is a difficult-to-treat otitis media characterized by eosinophilic accumulation in the middle ear mucosa and effusion. It is refractory to conventional treatments and is strongly associated with asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The diagnostic criteria for EOM were established by IINO in 2011. With the recognition of type 2 inflammatory diseases, the gold standard of treatment is the systemic and topical administration of corticosteroids. Recently, several retrospective studies have demonstrated the efficacy of biologic treatments in EOM. We aimed to share our experience regarding the response of EOM after the use of biologics. METHODS: This is a retrospective observational analysis including patients with refractory EOM treated with different biologics (benralizumab, omalizumab, mepolizumab, dupilumab) for concomitant severe asthma, urticaria and/or severe uncontrolled CRSwNP from 2011 to 2023. Treatment effectiveness in terms of EOM severity was measured using medical Global Evaluation of Treatment Effectiveness (GETE). RESULTS: We illustrated 4 clinical cases of uncontrolled comorbid EOM and demonstrated the complexity of multidisciplinary medical pathway with good response to biologics. We also observed that response to EOM and CRSwNP does not always follow that of asthma. CONCLUSIONS: The results of our small sample were consistent with those found in the literature and showed control of EOM with biologics. We need a larger multicentric sample and methodology to confirm these results and to compare the efficacy of different biologics.

Factors Associated with Dupilumab Response in Atopic Dermatitis: A Systematic Review and Meta-analysis.

BACKGROUND: Dupilumab was approved for treating moderate-to-severe atopic dermatitis (AD). However, a notable subset of patients remains unresponsive and factors associated with dupilumab response are still limited. OBJECTIVE: To systematically review and establish factors related to dupilumab response in AD. METHODS: We searched electronic databases, including PubMed/MEDLINE, Embase, Ovid and the Cochrane Center of Controlled Trials, from inception to March 2023. The primary outcome was factors linked to dupilumab response in AD. The odds ratio (OR) and 95% confidence interval (CI) related to a 75% reduction at 12-16 weeks in Eczema Area and Severity Index (EASI) score were synthesized using random-effects meta-analysis. RESULTS: Of 21 studies involving 5,575 AD patients, 3 were post hoc analyses of phase 3 dupilumab studies, 12 were retrospective, and 6 were prospective studies. Factors associated with favorable responses to dupilumab, defined by the percentage of patients achieving EASI75 at 12-16 weeks, included female with the OR (95% CI) of 2.16 (1.38, 3.38), younger age 2.81 (1.64, 4.81), absence of allergic rhinitis 2.64 (1.07, 6.50), lower body mass index 1.97 (1.18, 3.30), and lower blood eosinophil count 6.47 (3.36, 12.48), with very low certainty of evidence. Age of onset, baseline EASI score, total IgE level, and serum lactate dehydrogenase level were unrelated to dupilumab response. CONCLUSION: Female, younger age, absence of allergic rhinitis, lower BMI, and lower blood eosinophil count were associated with favorable response to dupilumab in patients with AD. These factors should be taken into account when considering dupilumab therapy in clinical practice.

A comparison of the impact of anti-IL5/5r therapies in allergic versus non-allergic patients with severe eosinophilic asthma in a real-life setting.

OBJECTIVE: This study aimed to compare the clinical characteristics and treatment outcomes of allergic patients (AP) and non-allergic patients (NAP) with severe eosinophilic asthma (SEA) treated with anti-IL5/IL5R biologic agents (mepolizumab, benralizumab, or reslizumab) over one year. Sub-analyses assessed treatment response variations between AP and NAP based on the biological used and compared outcomes among AP with and without fungal allergy. METHODS: Observational retrospective analysis. Clinical characteristics, laboratory findings, pulmonary function tests, Asthma Control Test (ACT) scores, oral corticosteroid (OCS) usage, and exacerbation frequency were assessed at the initiation of biological treatment and after one year. RESULTS: Sixty-five patients with SEA were included, 41 AP and 24 NAP. 55.4% were treated with mepolizumab, 33.8% with benralizumab, and 10.8% with reslizumab. Before anti-IL5/5R treatment, AP had worse baseline outcomes but there were no differences in pulmonary function. Mean annual exacerbation rate and percentage of patients requiring OCS and dose of prednisone were higher in AP than NAP. AP had significantly higher total IgE values. After one year of treatment, more AP discontinued OCS than NAP (p = 0.025). Both experienced a significant reduction in exacerbation frequency (p = 0.001) and improved respiratory function. 70.7% of AP and 60% of NAP improved ACT ≥3 points. There was no significant difference between AP and NAP using mepolizumab (p = 0.145) or benralizumab (p = 0.174) in reducing OCS. CONCLUSIONS: Anti-IL5/IL5R reduced the need for OCS and improved asthma control, regardless of allergic status. Fungal allergy led to lower ACT scores and higher exacerbations than other allergens; both groups improved with anti-IL5/ILR.

Temporal variation in the effectiveness of biologics in asthma: Effect modification by changing patient characteristics.

BACKGROUND: The underlying population of patients selected for each respiratory monoclonal antibody might change as other biologics are approved. OBJECTIVE: To evaluate effect modification by calendar time of the effectiveness of each respiratory biologics in asthma. METHODS: The Effectiveness of Respiratory biologics in Asthma (ERA) is a retrospective cohort of severe asthma patients from the Mass General Brigham clinics between January 2013 and September 2023. Periods were pre-specified as the anti-IgE (2013-2015), anti-IL5 (2016-2018), anti-IL4/13 (2019-2021) or anti-alarmin (2022-2023) era. We evaluated each biologic's effect on asthma-related exacerbations comparing the one-year period before and after therapy initiation using Poisson regression and Cox regression for time-to-first exacerbation. RESULTS: Of 647 biologic-naïve patients, 165 initiated omalizumab, 235 anti-IL5, 227 dupilumab, and 20 tezepelumab. Omalizumab's effectiveness improved as more biologics were approved: incidence rate ratio (IRR) 1.16 [0.94-1.43] anti-IgE era vs. 0.54 [0.37-0.80] anti-IL4/13-alarmin era. Omalizumab patients in the anti-IL4/13-alarmin era had lower blood eosinophil counts and less chronic rhinosinusitis with nasal polyps (CRSwNP). For anti-IL5s, effectiveness peaked in the anti-IL4/13 era (IRR 0.52 [0.42-0.64]) when patients had higher BMI and less concomitant CRSwNP. Dupilumab was most effective in the anti-IL4/13 era (IRR 0.60 [0.50-0.72]). There were fewer current smokers in dupilumab patients in the anti-IL4/13 era. Results were similar in time-to-event analyses and in sensitivity analyses accounting for the COVID-19 pandemic. CONCLUSION: There are temporal variations in the effectiveness of biologics partly explained by the shift in the underlying population, particularly for omalizumab. Though having more choices was associated with better patient selection for omalizumab, this was inconsistent for other biologics.

Nano- and Micro-Platforms in Therapeutic Proteins Delivery for Cancer Therapy: Materials and Strategies.

Proteins have emerged as promising therapeutics in oncology due to their great specificity. Many treatment strategies are developed based on protein biologics, such as immunotherapy, starvation therapy, and pro-apoptosis therapy, while some protein biologics have entered the clinics. However, clinical translation is severely impeded by instability, short circulation time, poor transmembrane transportation, and immunogenicity. Micro- and nano-particles-based drug delivery platforms are designed to solve those problems and enhance protein therapeutic efficacy. This review first summarizes the different types of therapeutic proteins in clinical and research stages, highlighting their administration limitations. Next, various types of micro- and nano-particles are described to demonstrate how they can overcome those limitations. The potential of micro- and nano-particles are then explored to enhance the therapeutic efficacy of proteins by combinational therapies. Finally, the challenges and future directions of protein biologics carriers are discussed for optimized protein delivery.

Psoriasis treatment and biologic switching: The association with clinical characteristics and laboratory biomarkers over a 13-year retrospective study.

The advent of biologics has greatly improved patient outcomes, yet some patients are compelled to switch therapies. Predicting these therapeutic failures is important; however, the factors associated with switching biologics have not been fully explored. This study examined patterns and determinants of biologics switching in psoriasis treatment retrospectively over 13 years. We focused on the association between clinical characteristics, basal laboratory data, and frequency of biologics switching. The findings revealed that elevated Psoriasis Area Severity Index scores and the presence of arthritis were observed in patients who experienced two or more treatment switches compared with those without treatment switches. Moreover, neutrophil to lymphocyte ratio was associated with higher biologics switching rates, indicating that systemic inflammation significantly impacts treatment adherence. A treatment approach, taking into account both the clinical presentation and inflammatory biomarkers, may be important for optimizing patient management in psoriasis.

Effect of biologic therapies on quality of life in severe asthma: Findings from the PRISM study.

Background: Anti-type 2 (T2) biologic therapies (biologics) improve exacerbation rates, lung function, and asthma-related quality of life (QoL) in patients with severe T2 asthma. However, studies comparing different biologics are lacking. We evaluated the QoL in patients with severe asthma comprehensively and compare the efficacy of different T2-directed biologics using QoL questionnaires. Methods: We compared the QoL between severe and mild-to-moderate asthma and between severe asthma with and without biologics treatment. Data of mild-to-moderate were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea, and data of severe asthma were collected from the Precision Medicine Intervention in Severe Asthma. We included 183 patients with severe asthma treated with T2 biologics or conventional therapy between April 2020 and May 2021 and assessed QoL of them using the Questionnaire for Adult Korean Asthmatics (QLQAKA), Severe Asthma Questionnaire (SAQ), and EuroQoL-5Dimensions (EQ-5D) at baseline and 6 months. Results: The EQ-5D index (0.803) of severe asthma was lower than that of other chronic diseases representing a worse QoL. The scores for all questions of QLQAKA, except "cough," were lower (less control) in the severe asthma group than in the mild-to-moderate asthma group at baseline and 6 months (P < 0.05). The total scores and subscores of all domains of the QLQAKA, SAQ, and EQ-5D improved significantly 6 months after biologic therapy but not after conventional therapy. The total QLQAKA, SAQ, and EQ-5D scores improved after 6 months in the anti-IL-5 (P < 0.05) and anti-IL-4/IL-13 (P < 0.05) treatment groups with no significant difference between groups (P > 0.05). Conclusion: QoL was worse in severe asthma than in mild-to-moderate asthma and other chronic diseases. T2 biologics equally improved QoL in patients with severe asthma.

Clinical characteristics of patients with a family history of psoriasis: an observational epidemiological study in Chinese Han population.

Introduction: Psoriasis, a chronic inflammatory skin disease, is believed to be influenced by both genetic and environmental factors. Despite this understanding, the clinical epidemiological status of psoriasis patients with a family history of the disease remains uncertain. Methods: In this study, we participated in a multicenter observational epidemiological study involved over 1,000 hospitals and enrolled a total of 5,927 psoriasis patients. These patients were categorized into two groups based on the presence or absence of a family history of psoriasis: family history cases (896) and sporadic cases (5,031). The clinical manifestations of these two groups were analyzed through clinical classification, comorbidities, treatment response, and other relevant factors. Results: The findings of our study indicate that individuals with a family history of psoriasis predisposition exhibit a notably elevated prevalence of psoriatic arthritis compared to those with sporadic occurrences. Moreover, patients with a family history of psoriasis display a more rapid and efficacious response to secukinumab. Additionally, individuals with moderate to severe psoriasis are at a heightened risk of developing cardiovascular and liver diseases in comparison to those with mild psoriasis, with no discernible impact of familial history on the likelihood of comorbidities. Discussion: Our study identified the clinical characteristics of individuals with a familial predisposition to psoriasis, offering novel insights into the management and therapeutic approaches for patients with this condition.