Biologics Research Articles

Successful Tralokinumab Treatment for Hand and Foot Atopic Dermatitis in a Patient with Skin of Color: A Case Report

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that disproportionately affects skin of color patients. New targeted biological therapies such as tralokinumab are available for the management of AD, but real-world evidence of their clinical effectiveness in skin of color patients is limited, particularly in patients with difficult-to-treat hand and foot involvement. In this report, we present a case of recalcitrant atopic dermatitis with hand-foot involvement in a skin of color patient successfully treated with tralokinumab.

Alcohol abuse and discretionary habits in psoriatic patients: impact on IL-17 and IL-23 inhibitor response.

Alcohol abuse is correlated with the onset and worsening of psoriasis, but its effects, as for smoking, on biological therapies are still poorly investigated. This study aimed to determine the prevalence of alcohol abuse and other discretionary habits (such as smoking and sedentary lifestyle) in patients with psoriasis treated with topicals, conventional systemic and biologic therapies. The second objective is to investigate the impact of discretionary habits, focusing on alcohol abuse, on the response to biological therapy. To identify alcohol dependence, the CAGE questionnaire was distributed among patients of our clinic. 305 patients were included with 18% at high risk of alcohol abuse. Clinically, guttate psoriasis and psoriatic arthritis were more common in patients at higher risk of alcohol abuse. Furthermore, patients with an alcohol problem who started biological therapy reported a higher PASI than those who drank less. None of the considered variables seemed to correlate with discontinuation of medication or with lower achievement of the analyzed outcomes (PASI100, PASI90, and PASI≤3). There was a stronger association between alcohol dependence and patients receiving conventional therapy than with patients receiving biologics. The efficacy of biologicals did not seem to be impacted by alcohol consumption, smoking, or sedentary lifestyle.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

A monoclonal antibody called mirikizumab is used to treat ulcerative colitis. It is marketed under the Omvoh brand. It is intended to bind to interleukin-23 (IL-23) and obstruct its function. Upper respiratory tract (nose and throat) infections, headaches, rashes, and injection site responses (when administered by subcutaneous injection) are the most frequent adverse effects. In the United States in October 2023 and the European Union in May 2023, mirikizumab was authorized for medicinal use. For the treatment of people with moderately to highly active ulcerative colitis who have not responded well to, have lost responsiveness to, or are intolerant to either biologic therapy or conventional therapy, mirikizumab is suggested. A subset of people with ulcerative colitis (UC) do not react to currently available medications, despite advancements in UC medical therapy. Many innovative medications have recently acquired regulatory approval for use in UC, or are in the latter stages of development. The novel antibody mirikizumab, which is given intravenously (IV), binds to the inflammatory protein interleukin 23 and inhibits its function, preventing inflammation from being triggered. For individuals with moderately to highly active UC, mirikizumab would therefore provide an additional therapy choice if legalized.

Recent developments in functional organic polymer coatings for biomedical applications in implanted devices

AbstractOrganic polymer coatings have been commonly used in biomedical field, which play an important role in achieving biological antifouling, drug delivery, and bacteriostasis. With the continuous development of polymer science, organic polymer coatings can be designed with complex and advanced functions, which is conducive to the construction of biomedical materials with different performances. According to different physical and chemical properties of materials, biomedical organic polymer coating materials are classified into zwitterionic polymers, non-ionic polymers, and biomacromolecules. The strategies of combining coatings with substrates include physical adsorption, chemical grafting, and self-adhesion. Though the coating materials and construction methods are different, many biomedical polymer coatings have been developed to achieve excellent performances, i.e., enhanced lubrication, anti-inflammation, antifouling, antibacterial, drug release, anti-encrustation, anti-thrombosis, etc. Consequently, a large number of biomedical polymer coatings have been used in artificial lungs, ureteral stent, vascular flow diverter, and artificial joints. In this review, we summarize different types, properties, construction methods, biological functions, and clinical applications of biomedical organic polymer coatings, and prospect future direction for development of organic polymer coatings in biomedical field. It is anticipated that this review can be useful for the design and synthesis of functional organic polymer coatings with various biomedical purposes.

What is proven in the treatment of systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical presentation and organ involvement. Early diagnosis and rapid achievement of low disease activity or remission reduces organ damage and improves prognosis. Therapeutic principles can be divided into so-called basic measures and immunosuppressive treatment. Novel drugs have been developed in recent years, with new classes of agents being added for the treatment of SLE. These include biologic therapies and approved therapeutic options for the treatment of lupus nephritis. In light of improved treatment options, good disease control can now frequently be achieved; with savings on glucocorticoids, combination therapies are increasingly being used. Of great importance is the consistent use of basic measures, which include the use of hydroxychloroquine, optimization of cardiovascular risk factors, UV protection, bone-protective measures, and the implementation of vaccinations. In the treatment of lupus nephritis, conservative therapeutic measures for nephroprotection play acrucial role in renal prognosis. Finally, non-pharmacological therapy options such as exercise therapy are of great importance for improving quality of life.

Multimodal nature of pain syndrome in patients with rheumatoid arthritis in relation to the course of the disease and clinical characteristics

Purpose of the study. To evaluate the character of pain syndrome in patients with rheumatoid arthritis in correlation with the course of the disease and comorbid pathology.Material and methods. Sixty-six patients with a verified diagnosis of RA were examined. Of them 84.9% were women (n=56) and 15.1% men (n=10). The median age was 59 [52; 63] years. Disease activity was assessed by DAS28-CRP, with a median of 5.2 [4.54; 6.0]. Patients with moderate (31.8%) and high activity (57.5%) predominated. Disease duration averaged Me 156 [93; 246] months. Seropositive RA was suffered by 89.3% of patients. The distribution by radiological stage was as follows: 2 radiological stage – 36.3% (n=24), 3 radiological stage – 30.3% (n=20), 4 radiological stage – 33.4% (n=22). Baseline anti-inflammatory therapy was taken by 84.8% of patients (n=56), genetically engineered biological drugs were received by 28.7% (n=16). To assess the multicomponent nature of pain syndrome, the following were used: Pain Detect questionnaire — to verify neuropathic pain (NP), CSI questionnaire — to verify central sensitisation (CS). The EQ-5D-3L questionnaire was used to assess quality of life, and the Charlson index was used to assess comorbid pathology. Structural changes were assessed by modified Sharpe method on hand and foot radiographs, synovium vascularisation was assessed by joint ultrasound.Results. 84.8% of patients had pain syndrome of mixed nature. NP correlated with pain intensity by VAS (rSp=0.458, p<0.001), DAS28-CRP (rSp=0.509, p<0.001), number of peripheral arthritis (rSp=0, 414, p<0.001), number of comorbidities (rSp=0.337, p=0.006), Charlson index (rSp=0.323, p=0.009), EQ-5D-3L (rSp= –0.268, p=0.031). CS–with VAS pain intensity (rSp=0.250, p=0.045), DAS28-CRP (rSp=0.251, p=0.044), number of painful joints (rSp=0.353, p=0.004), number of comorbidities (rSp=0.368, p=0.003), BMI (rSp=0.266, p=0.032), systolic blood pressure level (rSp=0.403, p<0.001), number of erosions on hand and foot radiographs (rSp= –0.299, p=0.016), EQ-5D-3L (rCp= –0.408, p<0.001). Patients with the presence of synovial vascularization by ultrasound had three-component pain in more than half of cases, and the combination of inflammatory pain and CS did not occur in them.Conclusions. 84.8% of patients had multicomponent pain, with pain associated only with clinical parameters of disease activity. Associated pathology and local chronic inflammation in the joint potentiate the development of other types of pain and have a mutual negative influence.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

Thesafety and efficacy of upadacitinib 15mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. Thesafety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n =277/309) that initially received ABA. Of patients on UPA15 in the LTE (n =547), 28.3% (n =155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in theAmerican College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in theHealth Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n =263/303, 86.8%; ABA to UPA15: n =273/309, 88.3%) showed similar responses to the total population. The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

Efficacy of netakimab in patients with psoriasis and disease duration up to 1 year: implementation of a strategy for early prescription of genetic engineering biological therapy

Currently, in actual clinical practice, there is an increasing consensus that early administration of a biologically active drug not only prevents the progression of the pathological process in the skin, but also prevents the development of psoriatic arthritis, and also has a beneficial effect on comorbid pathologies and complications associated with systemic inflammation. Early treatment can modify the course of the disease and prevent not only the development of severe forms and disability, but also stop the progression of psoriasis, taking into account all stages of pathogenesis. In this aspect, the prescription of IL-17A blockers is justified.Material and methods. The study included a total of 16 patients aged 18–35 years with a period of manifestation of skin psoriasis &lt;1 year, who received netakimab at a dosage of 120 mg subcutaneously at 0, 1, 2 weeks and then 120 mg every month for 52 weeks.Results. By week 4, 68.75% (n=11) of patients achieved PASI 75, 37.5 % (n=6) PASI90 and 18.75% (n=3) PASI100. By week 8, delta PASI75 was observed in 87.5% (n=14) of patients, 68.75% (n=11) – PASI90 and 50% (n=8) – PASI100. By week 24, 100% (n=16) of patients achieved PASI75,81.25% (n=13) – PASI90 and 68.75% (n=11) – PASI100. By week 52, PASI75 delta was observed in 100% (n=16) patients, 100% (n=16) had PASI90 and 87.5% (n=14) had PASI100.Conclusions. Patients with a shorter duration of the disease (up to 1 year) during netakimab therapy achieve PASI75, PASI90, PASI100 in a shorter time (comparison with clinical trial data). In the presence of factors for the aggressive course of psoriasis (rapid progression of the process, widespread process upon manifestation, lack of effect from topical therapy, constantly progressive course, risk factors for PsA, subclinical course of PsA), early prescription of genetic engineering biological therapy (netakimab) should be considered as the most appropriate strategy.

Inflammatory Cytokines and Clinical Outcome Following Biological Therapy in Adult Bio-Naïve Psoriasis Patients.

Inflammatory cytokines may hold the key to the clinical evolution of psoriasis. The aims of this study are to find a correlation between levels of inflammatory cytokines such as TNF-α, IL-23, IL-17A, and IL-17F and disease duration and severity scores in psoriasis; to test if the decrease in any of the aforementioned cytokines is correlated with an amelioration in disease severity scores; and to analyze if any of the four biologic agents used are linked with a greater decrease in overall cytokine levels. We enrolled 23 adult patients under treatment with ixekizumab, secukinumab, guselkumab, or adalimumab and measured psoriasis disease severity scores PASI (Psoriasis Area Severity Index) and DLQI (Dermatology Life Quality Index), as well as the levels of the aforementioned cytokines at the start of therapy and after 3 months of continuous treatment. Inclusion criteria were the presence of psoriasis, age above 18 years and the need to initiate biological therapy (lack of response to standard treatment). Biological therapies resulted in an amelioration of PASI and DLQI scores, as well as levels of TNF-α, IL-23 and IL-17F. Disease duration and PASI and DLQI scores did not correlate with cytokine levels except DLQI and IL-23 score, in a paradoxically inversely proportional manner. IL-23, in particular, could be a useful biomarker for checking treatment response in psoriasis.

Frequency of use and annual costs of biological therapy for psoriasis in Colombia in 2019.

Evidence describing the types and annual costs of biological treatments for psoriasis in Latin America is scarce. This study aimed to estimate the frequency of use and costs of biologic therapy for psoriasis in Colombia in 2019. This secondary data analysis uses the International Classification of Diseases terms associated with psoriasis, excluding those related to psoriatic arthritis, based on data from the registry of the Colombian Ministry of Health. We estimated the prevalence of psoriasis per 100,000 inhabitants; then, we retrieved the frequency of use of biologic therapy in patients with psoriasis and estimated the cost per year of each and overall therapies in 2019 in US dollars (USD). There were 100,823 patients with psoriasis in Colombia in 2019, which amounts to a prevalence of 0.2% in the general population. Of those patients, 4.9% received biologic therapy, most frequently males (60%). The most commonly used biological therapies for psoriasis in Colombia in 2019 were ustekinumab (35.2%), with an annual cost per patient of $12,880 USD; adalimumab (26%), with a yearly cost per patient of $7130 USD; and secukinumab (19.8%), with an annual cost per patient of $6825 USD. This is the first study to describe the use and cost of biological therapy for psoriasis in Colombia. It provides valuable cost-awareness information for the Colombian health system.

Guidelines How to Integrate Surgery and Targeted Therapy with Biologics for the Treatment of Hidradenitis Suppurativa: Delphi Consensus Statements from an Italian Expert Panel.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent and painful nodules and abscesses in intertriginous skin areas, which can progress to sinus tract formation, tissue destruction, and scarring. HS is highly debilitating and severely impairs the psychological well-being and quality of life of patients. The therapeutic approach to HS is based on medical therapy and surgery. First-line medical therapy includes topical antibiotics, systemic antibiotics, and biologics. Main surgical procedures include deroofing, local excision, and wide local excision. Despite the availability of multiple therapeutic options, the rates of disease recurrence and progression continue to be high. In recent years, the possibility of combining biologic therapy and surgery has raised considerable interest. In a clinical trial, the perioperative use of adalimumab has been associated with greater response rates and improved inflammatory load and pain, with no increased risk of postoperative infectious complications. However, several practical aspects of combined biologic therapy and surgery are poorly defined. In June 2022, nine Italian HS experts convened to address issues related to the integration of biologic therapy and surgery in clinical practice. To this purpose, the experts identified 10 areas of interest based on published evidence and personal experience: (1) patient profiling (diagnostic criteria, disease severity classification, assessment of response to treatment, patient-reported outcomes, comorbidities); (2) tailoring surgery to HS characteristics; (3) wide local excision; (4) presurgery biologic treatment; (5) concomitant biologic and surgical treatments; (6) pre- and postsurgery management; (7) antibiotic systemic therapy; (8) biologic therapy after radical surgery; (9) management of adverse events to biologics; and (10) management of postoperative infectious complications. Consensus between experts was reached using the Estimate-Talk-Estimate method (Delphi Method). The statements were subsequently presented to a panel of 27 HS experts from across Italy, and their agreement was assessed using the UCLA Appropriateness Method. This article presents and discusses the consensus statements.

Real-World Safety Profile of Biologic Drugs for Severe Uncontrolled Asthma: A Descriptive Analysis from the Spanish Pharmacovigilance Database.

Background: The present investigation provides a thorough analysis of adverse drug reactions (ADRs) reported in the Database of the Spanish Pharmacovigilance System (FEDRA) for biologic medications primarily indicated for severe refractory asthma, including omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab. Our main objective was to identify ADRs not documented in the drugs' Technical Sheets (summary of product characteristics, SmPC), potentially indicating unrecognized risks meriting pharmacovigilance attention. Methods: Data spanning from each drug's market introduction until 22 January 2024, were analyzed, sourced from direct submissions to the Spanish Pharmacovigilance System, industry communications, and literature reviews. We evaluated notifications impartially to ensure a comprehensive review of all the ADRs associated with these medications. Results: This investigation underlines the critical role of post-marketing surveillance in enhancing patient safety. It emphasizes the necessity for healthcare professionals to report ADRs comprehensively to foster a robust pharmacovigilance system. Furthermore, the study highlights gaps between the reported ADRs and the information provided in SmPCs, signaling potential areas for improvement in drug safety monitoring and regulatory oversight. Conclusions: Finally, these findings may contribute to informed decision making in clinical practice and regulatory policy, ultimately advancing patient care and safety in the management of severe uncontrolled asthma.

Comment on: Where are we now in biological drugs for myositis?

Comment on: Where are we now in biological drugs for myositis?

Mechanical release of homogenous proteins from supramolecular gels

A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling. Cold-chain management is the best solution at present for protein transport but requires substantial infrastructure and energy. For example, in research laboratories, a single freezer at −80 °C consumes as much energy per day as a small household1. Of biological (protein or cell) therapies and all vaccines, 75% require cold-chain management; the cost of cold-chain management in clinical trials has increased by about 20% since 2015, reflecting this complexity. Bespoke formulations and excipients are now required, with trehalose2, sucrose or polymers3 widely used, which stabilize proteins by replacing surface water molecules and thereby make denaturation thermodynamically less likely; this has enabled both freeze-dried proteins and frozen proteins. For example, the human papilloma virus vaccine requires aluminium salt adjuvants to function, but these render it unstable against freeze–thaw4, leading to a very complex and expensive supply chain. Other ideas involve ensilication5 and chemical modification of proteins6. In short, protein stabilization is a challenge with no universal solution7,8. Here we designed a stiff hydrogel that stabilizes proteins against thermal denaturation even at 50 °C, and that can, unlike present technologies, deliver pure, excipient-free protein by mechanically releasing it from a syringe. Macromolecules can be loaded at up to 10 wt% without affecting the mechanism of release. This unique stabilization and excipient-free release synergy offers a practical, scalable and versatile solution to enable the low-cost, cold-chain-free and equitable delivery of therapies worldwide.

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease.

IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.

Comprehensive Review on Bimolecular Fluorescence Complementation and Its Application in Deciphering Protein-Protein Interactions in Cell Signaling Pathways.

Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein-protein interactions (PPIs) within cell signaling pathways are essential for signal transmission and regulation. The spatiotemporal features of PPIs in signaling pathways are crucial for comprehending the regulatory mechanisms of signal transduction. Bimolecular fluorescence complementation (BiFC) is one kind of imaging tool for the direct visualization of PPIs in living cells and has been widely utilized to uncover novel PPIs in various organisms. BiFC demonstrates significant potential for application in various areas of biological research, drug development, disease diagnosis and treatment, and other related fields. This review systematically summarizes and analyzes the technical advancement of BiFC and its utilization in elucidating PPIs within established cell signaling pathways, including TOR, PI3K/Akt, Wnt/β-catenin, NF-κB, and MAPK. Additionally, it explores the application of this technology in revealing PPIs within the plant hormone signaling pathways of ethylene, auxin, Gibberellin, and abscisic acid. Using BiFC in conjunction with CRISPR-Cas9, live-cell imaging, and ultra-high-resolution microscopy will enhance our comprehension of PPIs in cell signaling pathways.

Incidence of Malignancies and the Association with Biological Disease-Modifying Antirheumatic Drugs in Japanese Patients with Rheumatoid Arthritis: A Time-Dependent Analysis from the IORRA Patient Registry.

Patients with rheumatoid arthritis (RA) may have an increased malignancy risk versus the general population, potentially elevated by biological disease-modifying antirheumatic drug (bDMARD) use. Using patient registry data, we determined malignancy risk, stratified by bDMARD use, among Japanese patients with RA versus the Japanese general population and investigated whether bDMARD use is a time-dependent risk factor for the development of malignancy. Patients aged ≥ 18years with ≥ 2 data entries of RA in the IORRA (Institute of Rheumatology, Rheumatoid Arthritis) patient registry, enrolled from January 2013-December 2018, were identified ('All RA' cohort). Patients were stratified into bDMARD (≥ 1bDMARD received) or non-bDMARD (no history of bDMARDs) sub-cohorts. Malignancy incidence rates and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) versus the Japanese general population were calculated. Risk of RA medication use was analyzed using a time-dependent Cox proportional hazards model, after adjusting for covariates. A total of 8020 patients were identified for the All RA cohort; 2187 and 5833 for the bDMARD and non-bDMARD sub-cohorts, respectively. For all three cohorts, incidence of overall malignancies was similar versus the Japanese general population. Incidence of specific malignancies was also similar, but incidence of lymphoma was higher for all three cohorts (SIRs[95% CIs] 3.72 [2.71-4.93], 5.97 [3.34-9.59], and 2.79 [1.82-4.02], respectively). In the bDMARD sub-cohort, no increase in SIRs was observed for other site-specific malignancies. Inthe All RA cohort, use of methotrexate, tacrolimus, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs were not associated with the risk of overall malignancy; the hazard ratio (95% CI) was 1.36(0.96-1.93) for bDMARD use. Increased disease activity was a time-dependent risk factor of overall malignancy with a hazard ratio (95% CI) of 1.35 (1.15-1.59). The use of bDMARDs was not a time-dependent risk factor for malignancy.

Biologics Versus JAK Inhibitors. Part II: Risk of Infections. A Narrative Review.

The risk of infections associated with biological drugs (BD) and Janus kinase inhibitors (JAKi) has been extensively explored in the literature. However, there is a dearth of studies that evaluate both pharmacological groups together and, furthermore, compare them. Here, we review the risk of infections associated with BD and JAKi used in dermatology. A narrative review was performed. All relevant articles evaluating the risk of infection and opportunistic infections with BD and JAKi between January 2010 and February 2024 were selected. Overall, the incidence of infections, serious infections, and opportunistic infections associated with BD and JAKi is low, but higher than in the general population. JAKi approved for dermatological disorders (abrocitinib, baricitinib, deucravacitinib, upadacitinib, ritlecitinib, and topical ruxolitinib) have been shown to be safe, and present a low rate of infections. We found an elevated risk, especially with anti-tumor necrosis factor (anti-TNF) agents, rituximab, and JAKi (particularly tofacitinib at high doses). Specific associations with infections include tuberculosis and tuberculosis reactivation with anti-TNF agents and tocilizumab; candidiasis with anti-interleukin (IL) 17 agents; hepatitisB virus reactivation with rituximab, anti-TNF, and JAKi; and herpes simplex and herpes zoster infections with JAKi (especially tofacitinib and upadacitinib at high doses). The incidence of infections with ustekinumab and anti-IL-23 was very low. Anti-IL-1, nemolizumab, tralokinumab, and omalizumab were not associated with an increased risk of infections. Dupilumab could decrease the incidence of cutaneous infections. Anti-TNF agents, rituximab, and JAKi (particularly tofacitinib) can increase the risk of infections. Close monitoring of patients undergoing these therapies is recommended. Prospective studies with long-term follow-up are needed to comparatively evaluate the risks of infection deriving from treatment with BD and JAKi.

Stakeholder perspectives on the sustainability of the United States biosimilars market.

Biologic therapies play a critical role in modern medical practice but also present challenges for payers, patients, and other stakeholders because of their high cost. Biosimilars can mitigate the cost pressures of reference biologic therapy because they are typically priced at least 25% lower, providing a means to administer cutting-edge biologic therapy while also managing cost of care. In fact, the US health care system has saved an estimated $23.6 billion from use of biosimilars. However, the market is still in a nascent phase of development, and early cost-saving successes are not guaranteed to persist unless sustainable market conditions are established. To better understand the perspectives of stakeholders about opportunities and threats to the sustainability of the US biosimilar market, a multistakeholder roundtable discussion was convened in December of 2023 and included health care payers, providers, self-insured employers, a manufacturer, and a biosimilar research and advocacy organization. The objective of this commentary, authored by the roundtable participants, is to posit specific opportunities and threats that stakeholders should consider to better facilitate sustainable biosimilar market conditions in the United States. We highlight key points, including (1) biosimilar price volatility with large quarter-on-quarter declines for most products; (2) perverse economic incentives that encourage providers to use more expensive reference products because reimbursement dynamics make them more profitable; (3) complex rebate structures that create barriers to biosimilar access; and (4) ongoing changes to the legal and regulatory environment, including evidence requirements to gain "interchangeable" status. We conclude with an overview of potential policy solutions to address the sustainability opportunities and threats. The authors welcome the opportunity to advance this dialogue toward action and encourage additional stakeholders to join the effort. We are optimistic that, through informed decision-making and compromise, we can collectively achieve a robust and sustainable US biosimilars market that appropriately benefits all stakeholders.

Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.