Anti-Tumor Necrosis Factor Alpha Therapeutic Drug Monitoring in Inflammatory Disease: A Systematic Review.

BACKGROUND: Monoclonal antibodies encompass an increasingly important treatment for a variety of dermatologic conditions including hidradenitis suppurativa (HS). The high failure rate and cost of anti-tumor necrosis alpha (TNF-α) agents and emergence of biologic treatments critically warrant treatment strategies that identify treatment failures early and optimize therapy. This review’s primary objective is to understand the current literature on biologic therapeutic drug monitoring (TDM) used in chronic inflammatory diseases and apply this knowledge to future dermatologic studies and treatment. METHODS: Randomized controlled trials (RCTs) or high-quality retrospective analyses of RCTs investigating the outcomes of biologic TDM were identified between January 1979 and January 2020 within the PubMed/MEDLINE database using keywords: "biologic," "therapeutic drug monitoring," and "randomized controlled trial," combined with common medical conditions for which biologics are prescribed: "rheumatoid arthritis," "inflammatory bowel disease," "psoriasis," "Crohn’s," "ulcerative colitis," "vasculitis," and "hidradenitis suppurativa." The methods and findings of each study were compared. RESULTS: Three RCTs were included all examining TDM of TNF-α inhibitors in inflammatory bowel disease (IBD). Two studied TDM of infliximab, and one adalimumab. An additional high-quality retrospective analysis of an infliximab RCT captured in our search was also included. Two of the three RCTs (TAXIT and PAILOT) found proactive TDM superior to clinically based dosing and reactive TDM, respectively. The third RCT (TAILORX) found no significant difference between proactive and reactive TDM. CONCLUSION: TDM of anti-TNF-α biologics in IBD has demonstrated success through RCTs. Knowledge gained from these studies applies to dermatologic treatment. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.6671.

Proceedings Report of the Fifth Symposium on Hidradenitis Suppurativa Advances (SHSA) 2020.

The Symposium on Hidradenitis Suppurativa Advances (SHSA) is a joint meeting of the United States Hidradenitis Suppurativa Foundation (HSF) and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This annual cross-disciplinary meeting brings together experts from around the world in an opportunity to discuss the most recent advances in the study of hidradenitis suppurativa (HS). The fifth annual meeting was held virtually on 9-11 October 2020. A record 347 attendees, including 79 people with HS, from 20 different countries attended. Key take-home points included: Clinicians can optimize each visit by listening, provide education, and discuss treatments; a patient decision aid for HS (HS-PDA) is a freely available tool (www.informed-decisions.org); COVID-19 severity in HS patients was not different for patients treated with/without a biologic; comorbidity screening recommendations will be published soon; neutrophil extracellular traps (NETs) may play a role in HS; memory B cells, T helper 1 cytokines, and interleukin 1 signaling contributes to HS pathogenesis and are targets for new therapies; novel therapies are showing promise including a new JAK1 inhibitor (INCB054707) and brodalumab; and HS-specific outcome measures have emerged to better monitor disease severity, flare, and progression including a patient reported measure (HiSQOL) and an HS-specific investigator global assessment. J Drugs Dermatol. 2021;20(8):868-873. doi:10.36849/JDD.5836.

Lower Extremity Ulcers.

Lower extremity ulcerations contribute to significant morbidity and economic burden globally. Chronic wounds, or those that do not progress through healing in a timely manner, are estimated to affect 6.5 million people in the United States alone causing, significant morbidity and economic burden of at least an estimated $25 billion annually. Owing to the aging population and increasing rates of obesity and diabetes mellitus globally, chronic lower extremity ulcers are predicted to increase. Here, we explore the pathophysiology, diagnosis, and management of the most (and least) commonly seen lower extremity ulcers.

Functional Imaging in Wounds: Imaging Modalities of Today and Tomorrow.

Wound care is a multidisciplinary field with significant economic burden to our healthcare system. Not only does wound care cost the US healthcare system $20 billion annually, but wounds also remarkably impact the quality of life of patients; wounds pose significant risk of mortality, as the five-year mortality rate for diabetic foot ulcers (DFUs) and ischemic ulcers is notably higher compared to commonly encountered cancers such as breast and prostate. Although it is important to measure how wounds may or may not be improving over time, the only relative "marker" for this is wound area measurement-area measurements can help providers determine if a wound is on a healing or non-healing trajectory. Because wound area measurements are currently the only readily available "gold standard" for predicting healing outcomes, there is a pressing need to understand how other relative biomarkers may play a role in wound healing. Currently, wound care centers across the nation employ various techniques to obtain wound area measurements; length and width of a wound can be measured with a ruler, but this carries a high amount of inter- and intrapersonal error as well as uncertainty. Acetate tracings could be used to limit the amount of error but do not account for depth, thereby making them inaccurate. Here, we discuss current imaging modalities and how they can serve to accurately measure wound size and serve as useful adjuncts in wound assessment. Moreover, new imaging modalities are also discussed and how up-and-coming technologies can provide important information on "biomarkers" for wound healing.

New Therapies for the Treatment of Diabetic Foot Ulcers: Updated Review of Clinical Trials.

Diabetic foot ulcers (DFU) are the most costly and serious complication for patients with Diabetes Mellitus (DM). Among patients with DM, 4% annually and up to one third in their entire lifetime may experience a DFU. The majority of DFU do not heal in a timely fashion and non-healing is associated with complications including skin, soft tissue, bone and systemic infection as well as the need for amputation. While education and advances in standard care for DFU have occurred, more research is critical to identify new and better therapies for patients with DFU. In this review, we examine ongoing clinical trials (through clinicaltrials.gov) on treatments for DFU. Our review focuses on new, upcoming therapies, including topical agents, dressings, engineered tissue, cell therapy, growth factors, devices, and herbal/natural remedies. The preclinical background information for each of these new therapies is also reviewed and discussed.

The human heart contains distinct macrophage subsets with divergent origins and functions.

Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2- and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2- and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2- macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2- and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2- and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic function in heart failure patients. Collectively, these observations provide initial evidence for the functional importance of macrophage heterogeneity in the human heart.

Pediatric and adult dilated cardiomyopathy represent distinct pathological entities.

Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked cardiomyocyte hypertrophy and myocardial fibrosis compared with donor controls. In contrast, pediatric DCM specimens demonstrated minimal cardiomyocyte hypertrophy and myocardial fibrosis compared with both age-matched controls and adults with DCM. Strikingly, RNA sequencing uncovered divergent gene expression profiles in pediatric and adult patients, including enrichment of transcripts associated with adverse remodeling and innate immune activation in adult DCM specimens. Collectively, these findings reveal that pediatric and adult DCM represent distinct pathological entities, provide a mechanistic basis to explain why children fail to respond to adult heart failure therapies, and suggest the need to develop new approaches for pediatric DCM.