INDIVIDUAL ARTICLE: NECOM 4: Algorithm Integrating Skincare for the Management of Immunotherapy-Related Cutaneous Adverse Events for Cancer Patients and Survivors.

BACKGROUND: In the Nordic European Countries, cancer is the leading cause of death. The last decade has brought revolutionizing cancer treatments including immune checkpoint inhibitors (ICIs). Patients on ICIs have a high risk of developing cutaneous immune-related adverse events. Treating these side effects is of high importance to improve patient's quality of life (QoL) and continue the anti-cancer treatment. METHODS: The Nordic European Cutaneous Oncodermatology Management (NECOM) project develops tools to prevent and treat cancer therapy-related cutaneous adverse events (cAEs). The first 2 NECOM papers presented various cAEs and skincare regimens involving hygiene, moisturization, sun protection, and camouflage products for preventing and managing cAEs. The NECOM 3 practical algorithm was on the prevention and treatment of acute radiation dermatitis. This NECOM 4 practical algorithm is intended to prevent and manage cutaneous immunotherapy-related adverse events (cirAEs), improving cancer patients' QoL and outcomes. RESULTS: The NECOM advisors discussed the results of a systematic literature review and obtained consensus on the evidence and expert opinion-based practical algorithm for cirAEs to support all healthcare providers treating cancer patients in the Nordic European Countries. The algorithm starts with a simple skincare regimen of cleansing, moisturizing, and protection, followed by the exclusion of severe cutaneous adverse reactions, and then specific interventions to treat the most common cirAEs (pruritus, maculopapular eruption, eczematous eruption, psoriasis, lichenoid eruption, and bullous eruption). CONCLUSIONS: CirAEs are the most common side effects induced by ICIs and may lead to cancer treatment interruption or even discontinuation. Patient education on the prevention of cirAEs using a skincare regimen and treatment recommendations given in the NECOM 4 algorithm may help prevent and manage cirAEs and improve the QoL and outcome of patients receiving ICIs. J Drugs Dermatol. 2024;23:8(Suppl 2):s4-10.

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

INDIVIDUAL ARTICLE: NECOM 3: A Practical Algorithm for the Management of Radiation Therapy-Related Acute Radiation Dermatitis.

BACKGROUND: In the Nordic European countries in 2020, cancer diagnoses accounted for 175,925 patients. About 50% of cancer patients receive radiation therapy (RT), which may lead to radiation dermatitis (RD). Notably, patients with breast, head, neck, and anal cancers may be prone to developing RD. However, few algorithms exist for the prevention and treatment of RD. METHODS: The Nordic European Cutaneous Oncodermatology Management (NECOM) project aims to improve cancer patient outcomes by offering tools to prevent and treat cancer therapy-related cutaneous adverse events (cAEs). The first 2 NECOM papers presented various cAEs and skincare regimens involving hygiene, moisturization, sun protection, and camouflage products for preventing and managing cAEs. The NECOM 3 practical algorithm for preventing and managing acute RD (ARD) is intended to promote healthy skin and reduce RT-related ARD, improving cancer patient outcomes.  Results: The NECOM advisors discussed the results of a systematic literature review and obtained consensus on the evidence and opinion-based practical algorithm for ARD to support all stakeholders in the Nordic European healthcare setting. The algorithm starts with skin-preserving therapy, followed by skin condition assessment and patient-specific interventions based on the grade of RD present.  Conclusion: ARD may lead to symptoms of pruritus and pain, decreased QoL and morbidity, and treatment interruptions. Patient education on the prevention of RD and treatment recommendations given in the NECOM 3 algorithm may help prevent and manage RD and improve the overall care of patients receiving RT. J Drugs Dermatol. 2023;22:11(Suppl 2):s3-s10.

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT).

BACKGROUND: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb). METHODS: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal-Wallis test. MFI 500 was used as threshold to define autoAb reactivity. RESULTS: A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p < 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009). CONCLUSIONS: Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311).

Dupilumab as a treatment for cutaneous immune-related adverse events induced by immune checkpoint inhibitors: A case series and review of the literature.

Immune checkpoint inhibitors have revolutionized cancer treatment. They can induce cutaneous immune-related adverse events. One patient with immune-related eczema and two with immune-related bullous pemphigoid were successfully treated with dupilumab. Guidelines recommend the use of systemic steroids to manage moderate-to-severe cutaneous immune-related adverse events. They could potentially interfere with immunotherapy. There is a need to find alternative treatments that are safe in a cancer setting.

The use of interleukin-23 inhibitors to treat immune-related psoriasis induced by immune checkpoint inhibitors and in patients with active cancer: A case series and review of the literature.

Immune checkpoint inhibitors have revolutionized cancer treatment but can induce immune-related adverse events including psoriasis. Managing immune-related psoriasis or psoriasis in a cancer setting is challenging with a lack of safety data. We describe three patients receiving interleukin-23 inhibitors to manage psoriasis in an active cancer setting, including one with immune-related psoriasis. Interleukin-23 inhibitors were effective for all patients. While being on interleukin-23 inhibitors, one patient had cancer partial response, one had deep partial response but then progressed and died from her melanoma, and one suffered melanoma progression.

Supplement Individual Article: NECOM Skincare Algorithm for Patients With Cancer and Survivors.

BACKGROUND: Cancer treatment-related cutaneous adverse events (cAEs) frequently occur, which can interfere with anticancer treatment outcomes and can severely impact quality of life for patients. METHODS: The Nordic European Cutaneous Oncodermatology Management (NECOM) project aims to improve cancer patient outcomes by offering tools for preventing and managing cAEs. The first NECOM paper explored clinical insights in cAEs and focused on skincare regimens involving hygiene, moisturization, sun protection, and camouflage products. A skincare algorithm for patients with cancer and survivors follows this article to promote healthy skin and reduce cancer treatment-related cAEs. RESULTS: The NECOM panel discussed and reached a consensus on an evidence- and opinion-based practical algorithm for oncology skin care to support all stakeholders in the Nordic European health care setting. The oncology nurse is central in coordinating individual patient’s cancer care and performing triage for cAEs, seeking urgent care via an oncologist and/or the emergency department if needed. The care organization of the presented cAEs depends on the patient's general health and skin condition and the health care system. CONCLUSION: Communication on state-of-the-art treatment in the fast-evolving area of oncology is necessary to provide tailored general measures and skin care for cAEs supported by evidence and practice-based expert recommendations.J Drugs Dermatol. 2023;22:1(Suppl 2):s3-10.

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway.

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

SUPPLEMENT INDIVIDUAL ARTICLE: Skincare for Cancer Patients in Scandinavia.

Preventive measures, earlier diagnosis, and markedly improved anticancer treatments have resulted in increasingly more patients living with or surviving cancer. Frequently cancer treatment-related cutaneous adverse events (cAEs) occur, which can severely impact patients' quality of life (QoL) and interfere with anticancer treatment outcomes. Currently, cAEs related to anticancer treatment may be under-appreciated to prevent or provide early and effective treatment. The Nordic European Cutaneous Oncodermatology Management (NECOM) project explored clinical insights in cAEs and focused on skincare regimens involving hygiene, moisturization, sun protection, and camouflage products. The NECOM panel discussed and reached a consensus on evidence and opinion-based best practice recommendations for oncology skincare programs to support all stakeholders in the Nordic European healthcare setting working with oncology patients throughout the entire continuum of care achieve optimal outcomes, improving patients' QoL. J Drugs Dermatol. 2021;20:12(Suppl):s4-14.

US Cutaneous Oncodermatology Management (USCOM): A Practical Algorithm.

BACKGROUND: An increasing number of patients survive or are living with cancer. Anticancer treatments frequently have cutaneous adverse events (cAEs) that may severely impact patients' quality of life and interrupt anticancer treatment. The US Cutaneous Oncodermatology Management (USCOM) project aims to improve cancer patients' and survivors' quality of life by offering tools for preventing and managing cAEs. METHODS: An algorithm was designed to reduce the incidence of cAEs, treat cAEs, and maintain healthy skin using general measures and over-the-counter agents to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and advanced providers. The panel used a modified Delphi approach, developed, discussed, and reached a consensus on statements and an evidence-based algorithm. RESULTS: The USCOM algorithm includes education on cAEs for patients and clinicians supporting prevention, treatment, and maintenance using skincare measures before, during, and after cancer treatment. A skincare regimen including hygiene, moisturization, and sun protection products should be safe and effective in helping to minimize cAEs and improving skin conditions such as erythema, xerosis, pruritus, and photosensitivity. The number and quality of studies evaluating skincare formulations and regimens for cAEs are increasing, but the evidence on the benefits of specific formulations is still scarce. CONCLUSIONS: The algorithm focuses on general measures and skincare to prevent or reduce the severity of cAEs. Increased awareness of cAEs by the multidisciplinary team treating and guiding the cancer patient throughout their care may improve patient outcomes. J Drugs Dermatol. 2021;20:9(Suppl):s3-19.

Usability, Satisfaction, and Usefulness of an Illustrated Eczema Action Plan.

BACKGROUND: An eczema action plan (EAP) is an individualized tool to help caregivers and patients self-manage eczema. While novel illustrated EAPs have been developed and validated, there is limited literature examining the value of EAPs from patient and caregiver perspectives. OBJECTIVES: The objective of this study was to test the usability, satisfaction, and usefulness of our validated EAP from the perspective of patients and caregivers. METHODS: Consecutive patients from the pediatric dermatology clinic of a tertiary children's hospital from July 2016 to July 2017 were offered enrolment in a prospective survey study; informed consent was obtained from participants. The illustrated EAP was explained to the participant by a trained research assistant. Participants were sent electronic postvisit surveys using Likert scale questions via REDCap on EAP usability and satisfaction (9 items) as well as on usefulness (3 items). RESULTS: Of 233 consecutive clinic patients, 192 participants (82%) were enrolled, and 112 (58%; 85 caregivers and 22 patients) completed the postvisit surveys. Characteristics were similar between responders and nonresponders. Overall, participants rated the usability (96%), satisfaction (85%), and usefulness (78%) of the EAP positively. Education level, experience with eczema, previous dermatology consultation, and participant type (caregiver vs patient) did not significantly affect the usability or usefulness ratings. However, caregivers' overall EAP ratings were significantly higher ( P = .02) than the patients'. CONCLUSION: The caregivers and participants demonstrate that the EAP is a useful and highly usable tool. Future research should examine the effectiveness of EAP use on objective atopic dermatitis outcomes using a pragmatic clinical trial design.

Derivation, Evaluation, and Validation of Illustrations of Key Counselling Points for a Pediatric Eczema Action Plan.

BACKGROUND: Current eczema action plans (EAP) are based on written instructions without illustrations. Incorporating validated illustrations into EAPs can significantly improve comprehension and usability. OBJECTIVE: To produce and validate a set of illustrations for key counselling points of a pediatric EAP. METHODS: Illustrations were developed using key graphic elements and refined by subject experts. Illustrations were evaluated during one-on-one structured interviews with parents/caregivers of children ages 9 and younger, as well as with children ages 10 to 17 years between September 2015 and June 2016. The concepts of transparency, translucency, and short-term recall were assessed for validation. RESULTS: Of 245 participants, 81.3% were parents and/or caregivers of children 0 to 9 years old, and 18.7% were children between 10 and 17 years old. A total of 15 illustrations and 2 storyboards were evaluated; 9 illustrations and 2 storyboards were redesigned to reach the preset validation targets. Overall, 13 illustrations and 2 storyboards were validated. CONCLUSION: A set of illustrations for use in an EAP was prospectively designed and validated, achieving acceptable transparency, translucency, and recall, with input from patients and a multidisciplinary medical team. The incorporation of validated illustrations into eczema action plans benefits patients with limited health literacy. Future studies should evaluate if illustrations improve understanding of eczema management and translate into improved clinical outcomes.

CD30+ Lymphoproliferative Disorders of the Skin.

Primary cutaneous CD30+ lymphoproliferative disorders encompass lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and indeterminate cases. LyP is a benign disorder characterized by recurrent crops of red or violaceous papulonodules. Patients with LyP are at an increased risk of a secondary malignancy. pcALCL is characterized by a solitary red to violaceous nodule or tumor larger than 20 mm. LyP is benign, is limited to the skin, and self-resolves, with a 5-year survival rate of 100%; pcALCL is limited to the skin and responsive to directed therapies, with a 5-year survival rate of over 95%. Aggressive chemotherapeutic regimens should be avoided.

Acitretin-induced hepatitis: when to monitor cholestatic enzymes.

IMPORTANCE: Acitretin is a systemic retinoid that is used in dermatology for a variety of conditions. A well-recognized potential adverse event from acitretin is elevated transaminases, indicating acute hepatocyte damage. Less well known is the possible cholestatic injury that can occur, signaled by elevated γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP). OBSERVATIONS: Our patient presented with an acute acitretin-induced hepatitis with a mixed pattern of elevated transaminases as well as GGT and ALP. A literature review demonstrated that most cases of acitretin-induced hepatitis, outside clinical trials, describe patients with a similar mixed hepatitis pattern. CONCLUSIONS: This is the first literature review on acitretin-induced hepatitis. Although acitretin-induced hepatoxicity is rare, the seemingly unusual presentation of a mixed pattern of hepatocyte injury and cholestasis may be more common than previously thought. The findings should encourage clinicians not only to monitor transaminases but also to consider measuring cholestatic enzymes (ALP/GGT) in patients with transaminase abnormalities.

Novel use of polymethyl methacrylate (PMMA) microspheres in the treatment of infraorbital rhytids.

AIM: To demonstrate safely with the use of polymethyl methacrylate (PMMA) microspheres in the infraorbital eyelid area using a deliberate conservative injection in the treatment of rhytids. METHODS: A retrospective case series of 289 patients in an outpatient cosmetic dermatology clinic evaluated and treated by one senior provider (NM) of infraorbital rhytids with PMMA from December 2010 to March 2011. Statistical analysis was performed for race, skin type, history of hypertrophic scar, autoimmunity, history of "sensitive skin" and history of prior procedures such as prior facelift, rhinoplasty, and blepharoplasty. RESULTS: Two hundred ninety-one patients underwent at least 1-6 injections of PMMA microspheres into bilateral under eye area. Early complications were edema and ecchymosis. Late complications were identified in 4 of 289 patients who developed small granulomas. All patients who developed granulomas had had a previous lower blepharoplasty (P = 0.00). A history of "sensitive skin" was approaching statistical significance (P = 0.15). CONCLUSION: This study has shown that PMMA microsphere injection is a safe subdermal technique in the correction of infraorbital rhytids. Safety was demonstrated in 289 patients with only 4 minor complications of small lateral granuloma which all resolved within 4 weeks after intralesion triamcinolone injection. However, this is an off-label use of a permanent filler not approved for use in the infraorbits and significant caution must be taken with full disclosure to the patient leading to informed consent. Caution in PMMA microsphere injection should be given in the patient with prior blepharoplasty. The advantage of PMMA microsphere is that the result seems to be predictable and natural.

Palmoplantar subcorneal pustular dermatosis following adalimumab therapy for rheumatoid arthritis.

BACKGROUND: Tumour necrosis factor (TNF)-α inhibitors represent potent new therapies for severe forms of psoriasis, psoriatic arthritis, and several other immune-mediated disorders. Paradoxical worsening or de novo development of psoriasis has been documented with their use. Palmoplantar pustulosis has been one of the commoner presentations of this unusual side effect. Subcorneal pustular dermatosis (SPD) has some similarity to pustular psoriasis, particularly the acral form of SPD. Thus far there have been no biopsy-proven cases of SPD associated with TNF-α inhibitor use. METHODS: We describe clinical and histopathological features of a pustular skin condition which occurred in a 48-year-old woman with rheumatoid arthritis who had started adalimumab four months prior. The adalimumab had been added to her usual treatment with methotrexate because of incomplete symptom control. RESULTS: Painful and pruritic skin lesions were noted on her palms and soles primarily, with some extension to the limbs and abdomen. Examination revealed relatively non-inflamed pustules with fluid levels, together with sparse crusted papules. Histopathology showed subcorneal pustules more suggestive of SPD than pustular psoriasis. The eruption resolved completely when adalimumab was withdrawn; methotrexate was continued. CONCLUSION: Subcorneal pustular dermatosis, in addition to psoriasis vulgaris and pustular psoriasis, may occur in patients treated with TNF-α inhibitors like adalimumab.