Maurizio Romagnuolo

Introduction: Vitiligo is a chronic autoimmune depigmentation skin disorder characterized by the acquired loss of melanocytes, with a complex multifactorial pathophysiology. Among the potential predisposing factors, some drugs, including monoclonal antibodies, have been associated to disease onset. Methods: The aim of the present review is to summarize and discuss current literature findings in de novo vitiligo following biological targeting inflammatory cytokines. Results: Overall, 18 articles were considered eligible for the present review, and details of demographics, clinical characteristics, vitiligo type and localization, biological drug administered and treatment outcomes were reported.The mean age of the 39 patients was 43 years (±16.3), with a male predominance (62%). Tumor necrosis factor-alpha (TNFα) inhibitors (infliximab, adalimumab, certolizumab pegol) were the most frequent suspected drugs (>50% of patients), followed by anti-IL-17A (ixekizumab, secukinumab) and anti-IL-12/23 (ustekinumab). Four cases were linked to anti-IL-4/13 (dupilumab). The median onset of vitiligo was 5 months post-initiation (range 1.5–24), with one-third of cases involving the face and neck, and two cases of segmental vitiligo. Biologic discontinuation or switching occurred in 26% of cases. Regarding outcomes, 41% experienced stabilization, 36% achieved varying degrees of repigmentation, and 8% progressed. Discussion: While de novo vitiligo is reported as a potential adverse event of biological therapies, evidence for a direct causal relationship remains weak, with cases involving non-anti-TNFα agents appearing anecdotal. The co-occurrence of underlying autoimmune comorbidities in these patients points towards a coincidental rather than a causal relationship, highlighting the need for further research to fully elucidate this association.

Growing evidence has linked bullous pemphigoid (BP) to immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, the immunological features of ICI-associated BP (ICI-BP) are not yet fully elucidated. In order to characterize the humoral response in ICI BP patients and investigate whether their epitope profile differs from idiopathic BP (IBP), 53 ICI-BP patients were enrolled, immunologically characterized and compared with 59 IBP patients. ICI-BP had a distinctive IgG humoral profile, with reduced reactivity toward BP230 and recognition of multiple BP180 epitopes beyond the immunodominant extracellular noncollagenous 16A domain (NC16A). Specifically, reactivity to BP180 ectodomain was present in 94% of ICI-BP and 78% of IBP (p=0.044). Moreover, BP180 C-terminal epitope was more frequently targeted in ICI-BP than IBP (72% vs 41%, p=0.002). Notably, the combined use of an in-house BP180 ectodomain ELISA and the commercial BP180 test increased diagnostic sensitivity from 83% to 100%. Enhanced IgG reactivity toward nonimmunodominant epitopes, and especially C-terminal epitope recognition, characterize the humoral immune response in ICI-BP. Our data suggest that combining NC16A and fulllength BP180 ectodomain ELISAs may help reduce diagnostic delay in ICI-BP patients, in whom a timely diagnosis is crucial to appropriately manage the disease and ultimately avoid discontinuation ofcancer therapy.

Pembrolizumab for a triple negative breast cancer, while Didona et al. successfully used the antiinterleukin (IL)-4/IL-13 inhibitor dupilumab in a case series of 4 patients with ICIs-induced bullous pemphigoid, also identifying BP180 midportion as a specific autoantigenic target in this specific subset of patients.Dan Wang described a case of toxic epidermal necrolysis (TEN) following PD-1 inhibitor serlupimab administration for a small cells lung cancer (SCLC), focusing on the integrated multidisciplinary management with Western and Chinese nursing care and providing an interesting and educational perspective on the traditional Chinese medicine principles and practical approaches to skin diseases.Regarding Stevens-Johnson syndrome (SJS)/TEN spectrum -a rare but life-threating severe cutaneous records and performed a univariate analysis between in-hospital death (overall mortality 18.7%) and each SCORTEN parameter, showing that only tachycardia, malignancy and high serum urea remained independent predictors of mortality following multivariate regression analysis. These findings suggest that some SCORTEN parameters may be recalibrated to improve risk stratification in the current therapeutic context. The second most cited class of drug in our research topic articles was Janus Kinase inhibitors (JAKi), which represent a breakthrough in the treatment of inflammatory skin diseases. Both potential cutaneous side effects of JAKi and their use as a "rescue therapy" in drug-related skin AEs have been documented in our collection.Tang et al. conducted a retrospective disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database on the association between oral JAK-1 inhibitors and infection risk in atopic dermatitis. Their findings confirmed the established association with herpetic infections and reactivations (e.g. herpes simplex and herpes zoster), pneumonia and influenza virus, but also suggested potential unlabelled association with sepsis and appendicitis, which requires further confirmation in real-life setting and independent studies.Regarding the infection risk of JAKi, we reported the case of a 53-year-old man with vitiligo who developed tinea faciei at the application site of ruxolitinib 1.5% cream, which eventually led to the permanent discontinuation of therapy (Romagnuolo et al.). Topical ruxolitinib represents a novel and effective topical JAK1/2 inhibitor approved for non-segmental vitiligo with a generally favourable safety profile: clinical trials only reported mild-to-moderate AEs including site-application acne, nasopharyngitis and site-application pruritus, although real-world data on infection risk are still lacking.JAKi site-application acne is also discussed in the timely and up-to-date review on acneiform drug A further contribution on biologics-adverse reaction has been reported by, Zhao et al., who performed a disproportionality analysis for evaluating the safety of the anti-IL-17A ixekizumab basing on the post-market report of AEs retrieved from the FAERS and VigiAccess databases. This study confirmed known AEs (e.g. fungal infections, injection site reactions, upper respiratory tract infections and inflammatory bowel diseases) but also potential association with other AEs such as cellulitis, herpes zoster, ear infection and diverticulitis, which warrant further real-world investigation.Xi et al. documented the occurrence of bullous pemphigoid in a 78-year-old woman affected by psoriasis following treatment with the anti-IL-23 guselkumab, while also performing a comparative single cell transcriptomic analysis on tissue samples of both diseases, in order to reveal distinctive cellular landscape and disrupted pathways associated with this reaction. In addition to novel and emerging treatment-related AEs, our research topic highlights 3 articles dedicated to topical steroids, which underscores their widespread use and valid role in current dermatological practice.Chen et al. reported a rare case of iatrogenic Cushing syndrome, likely induced by the abuse of topical clobetasol propionate over a 5-year for psoriasis treatment, suggesting that physician should remain vigilant regarding topical steroid therapies prescribed to patients, as well as monitoring the use of overthe-counter medications both for patients' safety and for a thorough anamnesis during clinical practice.On the similar subject of topical steroid abuse or "addiction", Myles et al. published a perspective on topical steroid withdrawal (TSW) syndrome, covering its history and varying definitions, as well as the academic scepticisms and controversies surrounding it. Furthermore, they outline current knowledge gaps in TWS and propose criteria to assist both patients and clinicians in recognizing this debated condition.Finally, a retrospective study on fifty-five male lichen sclerosus et atrophicus (LSA) of the genitalia has been proposed by Pessina et al. This study evaluated the effects of topical steroid versus circumcision on quality of life (QoL) and postoperative recurrence risk. The authors reported that topical steroids were not significantly associated with QoL improvement measured by dermatological life quality index (DLQI) compared to circumcision and that the median steroid-free survival after circumcision was 19 months. Nevertheless, they concluded that topical steroids remain a mainstay treatment across the various stages of LSA, emphasizing the need for a tailored treatment in LSA patients.Other contributions covering topics beyond those mentioned above reflect the broad spectrum of cutaneous drug reactions, especially in oncological patients. In conclusion, this Research Topic highlights how the shift toward targeted therapies and immunotherapies has redefined the landscape of cutaneous adverse events, introducing complex diagnostic challenges, but also opportunities for pathophysiological inquiry on drug-related skin adverse events....

Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder of the pilosebaceous unit, with multiple factors contributing to its onset, activity and progression. Alongside a predisposing genetic background, hormonal and microbiome alterations, dysregulation of innate and adaptive immune response, as well as environmental/epigenetic factors contribute to its immunopathogenic landscape. In the past years, translational investigations identified several distinct inflammatory networks, not only in the chronic but also in the early stages of disease, making them potential therapeutic targets. Emerging evidence underlies the important role of keratinocytes in the pathogenesis and progression of HS, acting not only as targets of inflammatory signaling pathways but also as active producers of pro‐inflammatory cytokines, chemokines and effector molecules that may influence disease onset and activity. Despite these insights, different aspects of their involvement remain underexplored, necessitating further targeted research. This review aims to highlight the experimental evidence supporting the crucial role of keratinocytes in the inflammatory response and overall pathophysiology of HS.

Ruxolitinib 1.5% cream, a topical Janus Kinase (JAK) 1/2 inhibitor, represents a novel targeted treatment for non-segmental vitiligo, a common acquired depigmentation disorder of autoimmune origin clinically characterized by milky-white patches on the affected body areas. The efficacy of topical ruxolitinib in vitiligo has been demonstrated in clinical trials and real-life observation, with an overall safety profile. Mild-to-moderate reported adverse events include site-application acne, nasopharyngitis, and site-application pruritus, while increased susceptibility to viral skin infections, due to its mechanism of action leading to local immunosuppression, remains debated. No data are currently available on the potential susceptibility to fungal infection. We present here a case of a 53-year-old man who developed tinea barbae by Trichophyton tonsurans following ruxolitinib application, which eventually led to permanent treatment discontinuation.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease belonging to the group of neutrophilic dermatoses. The pathogenesis of PG involves a predisposing genetic background that facilitates a dysregulated innate and adaptive immune response, with an imbalance between pro-inflammatory and anti-inflammatory mediators, leading to neutrophil-driven inflammatory damage. Several immunosuppressants and immunomodulatory drugs are currently available for the treatment of PG, in combination with topical therapies, wound management and pain control strategies. Systemic corticosteroids and cyclosporine remain the first-line treatment options with the best evidence. However, in recent years, the rise of knowledge about different pathogenic mechanisms has led to a significant increase in studies attesting the efficacy and safety of biologic therapies including, among others, antagonists of tumour necrosis factor (TNF)-α and interleukin (IL)-23, becoming the drug of choice in specific clinical setting. Similarly, different small molecules such as JAK-STAT (Janus kinase/signal transducer and activator of transcription) inhibitors are showing promising results for the treatment of PG. We review established and emerging pathogenesis-driven treatments, also providing a therapeutic algorithm and informing future directions in the management of PG.

Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease of the terminal hair follicle, whose pathogenesis is complex and multifactorial. Alongside a predisposing genetic background, environmental/epigenetic factors, alterations in the skin microbiome, and dysregulation of both innate and adaptive immune responses contribute to the persistent inflammatory network. Despite advancing knowledge, the exact molecular and cellular mechanisms underlying HS have yet to be untangled. Moreover, the lack of experimental disease models that closely mimic disease phenotypes or pathophysiological processes has hindered the development of effective therapeutic strategies. Recent advances in immunology highlighted the important role of B cells in HS pathogenesis, not only in the chronic but also in the early stages of the disease, implying great potential for the development of novel therapeutic targets. This study gathers the preclinical and clinical scientific evidence that supports the role of cutaneous B‐cells in HS pathogenesis and the therapeutic potential of their targeting.

Background: Dupilumab is a monoclonal antibody used for the treatment of moderate/severe atopic dermatitis (AD). In recent years, several studies have confirmed the positive association between AD and overweight/obesity, and a report demonstrated the effect of weight reduction on the improvement of AD symptoms. Methods: The weight of 170 patients under treatment with dupilumab was recorded at baseline and after 48 weeks (T48). Clinical monitoring was mainly conducted using the Eczema Area and Severity Index (EASI). The study aimed to assess a possible correlation between the clinical outcome of dupilumab therapy and BMI. Results: Although not statistically significant, patients with a BMI < 25 have a higher EASI percentage improvement than patients with a BMI ≥ 25 at any time point, and the percentage of overweight and obese patients that does not reach EASI-75 at T48 is higher compared to normal-weight patients (13.5% vs. 5.9%). Despite this, in the multivariate regression analysis, no baseline characteristic, including BMI, appears to increase the risk of not reaching EASI-75. In addition, the results show no differences in BMI between baseline and T48 in any age/sex group. Conclusions: The results suggest that overweight and obese patients have a lower response to dupilumab when considering the EASI score, but this difference does not appear to be clinically significant. Furthermore, dupilumab treatment does not seem to impact weight.