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.

Nemolizumab with concomitant topical therapy in adolescents and adults with moderate-to-severe atopic dermatitis (ARCADIA 1 and ARCADIA 2): results from two replicate, double-blind, randomised controlled phase 3 trials.

BACKGROUND: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials. METHODS: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator's Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349). FINDINGS: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred. INTERPRETATION: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved. FUNDING: Galderma.

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.

Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).

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.

Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) remain a prevalent and common sequelae of immune checkpoint inhibitor (ICI) therapy, often necessitating treatment interruption and prolonged immune suppression. Treatment algorithms are still poorly defined, based on single-institution case reports without adequate safety assessments, and subject to publication bias. METHODS: Data in this registry were collected through a standardized REDCap form distributed to dermatologists via email listserv. RESULTS: Ninety-seven cirAEs were reported from 13 institutions in this registry. Topical and systemic steroids were the most common treatments used; however, targeted treatment matched to disease morphology was identified at numerous sites. Novel cirAE therapy uses that to our knowledge have not been previously described were captured including tacrolimus for the treatment of follicular, bullous, and eczematous eruptions and phototherapy for eczematous eruptions. Moreover, further evidence of cirAE treatment applications sparsely described in literature were also captured in this study including dupilumab and rituximab for bullous eruptions, phototherapy for lichenoid and psoriasiform eruptions, and acitretin for psoriasiform eruptions, among others. No serious adverse events were reported. Numerous targeted therapeutics including dupilumab, rituximab, and psoriasis biologics, among others, were associated with a cirAE grade improvement of ≥2 grades in every patient treated. CONCLUSION: This study suggests that a multi-institutional registry of cirAEs and management is not only feasible but that the information collected can be used to detect, evaluate, and rigorously assess targeted treatments for cirAEs. Further expansion and modification to include treatment progression may allow for sufficient data for specific treatment recommendations to be made.

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.

Skin Surface pH

The role of skin surface pH, also referred to as "acid mantle," was described more than 90 years ago and due to developing insights has now returned into focus.1

Clinical Insights About the Role of pH in Acne

Acne vulgaris is the most common dermatological disorder globally.1,2 Psychological and emotional distress due to acne, including poor self-esteem, social anxiety, depression, and suicidal ideation have been reported in various studies.3,4, Acne is a complex multifactorial disease with its pathophysiology incompletely elucidated.