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.

Unique protein signatures evolve during the course of a delayed-type hypersensitivity reaction in human skin.

Diphencyprone (DPCP) is a hapten that causes a delayed-type hypersensitivity reaction when applied topically. It has clinical uses in the treatment of various conditions such as melanoma metastases, warts, and alopecia areata, but the mechanisms are currently not well understood in humans. To further characterize the immunologic effects of DPCP, the authors performed a proteomic analysis of normal skin of eight healthy volunteers following a single application of DPCP and compared them with placebo-treated skin from the same volunteers. A total of 96 proteins were examined using the Olink immuno-oncology panel at 3 days (peak response), 14 days (partially resolved response), and 120 days (completely resolved response). Our analysis revealed significant upregulation of markers of immune cell activation (interleukin [IL] 8), vascular and tissue remodeling (matrix metallopeptidase 12 [MMP12], nitric oxide synthase 3 [NOS3]), antineoplastic markers (granzyme B [GZMB]), and the Th1 axis (interferon gamma [IFNG], chemokine (C-X-C motif) ligand [CXCL] 9, CXCL10, CXCL11) at days 3 and 14 compared with placebo (p < 0.05). In addition, several negative regulators of immune function such as programmed cell death 1 (PD1), programmed cell death ligand 1 (PDL1) (p < 0.001), and lymphocyte activation gene 3 (LAG3) (p < 0.05) were significantly upregulated at days 3 and 14. This induction of negative regulators may explain the seemingly paradoxical therapeutic benefits of DPCP in autoimmune conditions such as alopecia areata. The current analysis also indicated IL-4 upregulation only at day 3, followed by IL-12 upregulation only at day 14, suggesting a transient Th2 response followed by Th1 polarization. Overall, these data suggest a complex and evolving immunological delayed-type hypersensitivity response to a single application of DPCP over time. Future proteomic studies of samples from patients with melanoma metastases, warts, and alopecia areata treated long term with DPCP are needed to further evaluate its pharmacologic mechanisms.

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.

Development of Chancre-Variant Cutaneous Tuberculosis After BCG Vaccine Administration in a Patient With Migraines.

In countries other than the United States, the BCG vaccine is typically used as a method for preventing childhood tuberculosis; in the United States, the BCG vaccine has gained popularity as a speculated therapy for autoimmune and inflammatory disorders. Research suggests that the vaccine can train the innate immune response, thereby improving symptoms of disorders such as diabetes and fibromyalgia. However, the potential side effects associated with the use of this vaccine are not totally innocuous. Although 95% of recipients should expect common skin complications after administration of the BCG vaccine, other more serious cutaneous sequelae may occur. Potential cutaneous side effects associated with vaccine use can include fistulation, abscess formation, and even ulceration. This brief report highlights a patient in whom cutaneous tuberculosis developed, specifically tuberculous chancre, secondary to receiving the BCG vaccine as a possible treatment for fibromyalgia. After undergoing surgical debulking of the tumor, the patient subsequently received the standard of care to the wound base and was started on 6 months of isoniazid monotherapy. Cutaneous tuberculosis is exceedingly rare, and the chancre variant accounts for only about 1% of diagnosed cases. Although common in pediatric populations, the chancre variant of cutaneous tuberculosis is not typically seen in adult populations, most likely because the BCG vaccine is often administered to children to prevent childhood tuberculosis. As use of the BCG vaccine in adults becomes more prevalent to potentially treat or mitigate certain disorders, it is imperative that health care providers recognize the potentially severe side effects associated with its use.

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.

Readability of Online Patient Education Materials for Interventional Pain Procedures.

Background The internet has had an enormous influence on the field of medicine. In this regard, Statista, a market and consumer data company, estimated in 2019 that more than half the world's population (>four billion people) were active internet users. Accessing the World Wide Web has become the second nature for most. In the medical field, many patients look to the internet for information regarding certain procedures. The purpose of this study, therefore, was to assess the readability level of more than 492 online sources with information on a wide array of interventional pain procedures. Objective The aim is to determine the readability of online patient educational materials for interventional pain procedures. Study design This is a retrospective review. Methods We downloaded and reformatted to plain text 492 internet-based patient educational materials for 17 different interventional pain procedures. Plain text was processed using Readability Studio (Oleander Software Ltd., Vandalia, Ohio, USA), which employs 10 quantitative readability scales that are widely used and accepted in the medical literature. Results The software determined the average reading level (or grade level) of the 492 online sources we examined to be 12.1, with a range of 10.9 to 13. Limitations Google is not the only online search engine patients utilize for information, and the top links for each search could change over time. Also, some patients prefer videos rather than text to learn about their disease and treatment options. Finally, depending on their provider, the links that patients are directed to may be significantly more or less readable. Conclusions The average American adult reads at the eighth grade level. The National Institutes of Health and the American Medical Association have recommended education materials be made available at the third to seventh grade level. Our analysis shows patient educational materials found online for interventional pain procedures to be overly technical, with an average reading level (or grade level) of 12.1.

Augmenting the scope of dermatologic care and training via student-run health clinics.

Skin cancer is a major public health problem. Unfortunately, individuals who lack health insurance have lower skin cancer screening rates compared to insured individual and, therefore, have a higher risk of more advanced cancer diagnoses. Student-run health clinics may be the answer to this dilemma. Student-run health clinics can not only help by providing essential dermatologic services to the general population, both insured and uninsured, but also provide early exposure to dermatology education for medical students.