Evidence on Hidradenitis Suppurativa as an Autoinflammatory Skin Disease.

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin disease that often exhibits heterogeneity in its clinical presentation, especially in the context of its rare syndromic forms. The pathogenesis of HS results from a complex interplay of genetic predisposition, innate and adaptive immunity dysregulation, smoking, obesity and environmental factors. In the early phase of the disease, the innate immune system is hyperactivated, contributing to tissue damage and triggering the activation and amplification of the adaptive immune response, which plays a pivotal role in the chronic stages of the disease. Recent studies focused on elucidating the importance of innate immunity impairment and autoinflammation in HS and increasing evidence has emerged on the occurrence of the disease in the context of well-known monogenic and polygenic autoinflammatory syndromes (AIDs). This review provides a comprehensive examination of the current scientific background supporting the contribution of autoinflammation to HS etiology, including genetic data, molecular studies and clinical evidence, as well as the association between HS and AIDs. However, further research is needed to shed light on the pathogenic mechanism of this challenging condition and to identify potential perspectives for future therapeutic approaches.

Uncovering the Differences: How DLQI and WHO-5 Scores Vary in Moderate-to-Severe Psoriasis Patients Treated with Tildrakizumab 100 mg vs. 200 mg?

Background/Objectives: Psoriasis (PsO) is a chronic inflammatory skin disease that severely impacts patients' quality of life (QoL). Its global prevalence is about 2%, with significant regional variations. PsO manifests in the form of erythematous and scaly plaques, causing intense pruritus and discomfort and limiting daily activities. The condition often includes comorbidities such as psoriatic arthritis, cardiovascular diseases, and metabolic syndrome, further deteriorating QoL. Psychological well-being is notably affected, with high levels of depression and anxiety due to the visible lesions, leading to social stigma and isolation. QoL indexes like WHO-QoL and SF-36 assess various well-being aspects, while patient-reported outcomes (PROs) provide a comprehensive understanding of PsO's impact. However, there are no universally shared PROs in outpatient practice to fully understand the impact of the disease and associated therapies. This study aims to evaluate differences between DLQI and WHO-5 in adult patients with moderate-to-severe PsO treated with tildrakizumab 100 mg or 200 mg. Methods: The study was conducted at the University Hospital of Siena, Italy, from May 2023 to April 2024. Data from 15 patients treated with tildrakizumab 200 mg and 15 patients treated with tildrakizumab 100 mg, observed for at least 28 weeks, were recorded. Demographic data, PASI, DLQI, and WHO-5 scores were analyzed. Patients in the 100 mg group (G100) were selected to match the demographic characteristics of the 200 mg group (G200). Reduction rates of DLQI and WHO-5 were assessed at baseline values and after 4, 16, and 28 weeks. Results: Both groups experienced improvements in QoL. The group treated with 200 mg showed more pronounced and rapid reductions in DLQI and WHO-5 scores compared to the 100 mg group. WHO-5 demonstrated faster improvements in overall well-being than DLQI, indicating its greater sensitivity to changes in mental well-being and overall QoL. No differences in adverse events were observed between the two groups, with no major adverse events reported. Conclusions: In our study, WHO-5 proved more sensitive than DLQI in capturing well-being changes in PsO patients treated with tildrakizumab. However, a combined use of both WHO-5 and DLQI questionnaires should be encouraged in clinical practice. Furthermore, this study confirmed the superior QoL improvement associated with tildrakizumab 200 mg compared to 100 mg. Future research should explore the long-term impact on QoL and comparative effectiveness among other biologic therapies in diverse patient populations.

Fibromyalgia and Skin Disorders: A Systematic Review.

Background: Fibromyalgia is a complex multifaceted syndrome primarily characterised by chronic musculoskeletal pain, fatigue, and functional symptoms. Although FM is known to be associated with several comorbidities, the aim of this systematic review was to comprehensively examine the available evidence regarding the relationship between FM and dermatological manifestations. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and MedLine and Web of Science (WOS) databases were searched up to June 2023. After removing duplicate records, 21 articles were deemed eligible for inclusion in the qualitative synthesis. Results: Overall, the included studies revealed an increased frequency of FM among patients with cutaneous diseases, including psoriasis, chronic urticaria, contact allergy, acneiform disorders, hidradenitis suppurativa, and vitiligo. Additionally, the presence of comorbid FM may intensify skin conditions, which has a negative impact on quality of life and vice versa. Conclusions: Although the causal mechanisms of FM are still far from being understood, this systematic review suggests a relationship between FM and skin disorders. However, further research is encouraged in this area.

Blocking the IL-4/IL-13 Axis versus the JAK/STAT Pathway in Atopic Dermatitis: How Can We Choose?

Atopic dermatitis (AD) is an immune-mediated skin disorder with a chronic-relapsing course and a multifactorial pathogenesis. In contrast to the traditional concept of AD as solely a type 2 immune-activated disease, new findings highlight the disease as highly heterogeneous, as it can be classified into variable phenotypes based on clinical/epidemiological or molecular parameters. For many years, the only therapeutic option for moderate-severe AD was traditional immunosuppressive drugs. Recently, the area of systemic therapy of AD has significantly flourished, and many new substances are now marketed, licensed, or in the last step of clinical development. Biological agents and small molecules have enriched the therapeutic armamentarium of moderate-to-severe AD, such as dupilumab, tralokinumab, lebrikizumab (monoclonal antibodies targeting the IL-4/13 pathway), abrocitinib, upadacitinib, and baricitinib (JAK inhibitors). Indeed, the AD treatment paradigm is now split into two main approaches: targeting the IL-4/13 axis or the JAK/STAT pathway. Both approaches are valid and have strong evidence of preclinical and clinical efficacy. Therefore, the choice between the two can often be difficult and represents a major challenge for dermatologists. Indeed, several important factors must be taken into account, such as the heterogeneity of AD and its classification in phenotypes, patients' comorbidities, age, and personal preferences. The aim of our review is to provide an overview of the clinical and molecular heterogeneities of AD and to explore the factors and parameters that, in clinical practice, may help inform clinical decision-making.

Therapeutic Potential of Targeting the JAK/STAT Pathway in Psoriasis: Focus on TYK2 Inhibition.

Psoriasis is an inflammatory skin disease with a chronic relapsing course and an often-detrimental impact on patients' quality of life. Thanks to incredible advances in research over the past few decades, the therapeutic armamentarium of psoriasis is now reasonably broad and structured, with several therapeutic agents that have demonstrated successful long-term control of this condition. However, there are still unfulfilled gaps resulting from the inherent limitations of existing therapies, which have paved the way for the identification of new therapeutic strategies or the improvement of existing ones. A great deal of attention has recently been paid to the JAK/STAT pathway, playing a crucial role in chronic inflammatory skin diseases, including psoriasis. Indeed, in a disease with such a complex pathogenesis, the possibility to antagonize multiple molecular pathways via JAK/STAT inhibition offers an undeniable therapeutic advantage. However, data from clinical trials evaluating the use of oral JAK inhibitors in immune-mediated disorders, such as RA, have arisen safety concerns, suggesting a potentially increased risk of class-specific AEs such as infections, venous thromboembolism, and malignancies. New molecules are currently under investigation for the treatment of psoriasis, such as deucravacitinib, an oral selective inhibitor that binds to the regulatory domain of TYK2, brepocitinib (PF-06700841) and PF-06826647 that bind to the active site in the catalytic domain. Due to the selective TYK2 blockade allowing the inhibition of key cytokine-mediated signals, such as those induced by IL-12 and IL-23, anti-TYK2 agents appear to be very promising as the safety profile seems to be superior compared with pan-JAK inhibitors. The aim of our review is to thoroughly explore the rationale behind the usage of JAK inhibitors in PsO, their efficacy and safety profiles, with a special focus on oral TYK2 inhibitors, as well as to provide a forward-looking update on novel therapeutic strategies targeting the TYK2 pathway in psoriasis.

Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients.

BACKGROUND: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. OBJECTIVES: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. METHODS: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. RESULTS: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. CONCLUSION: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

Risk of Skin Cancer in Patients with Psoriasis: Single-Center Retrospective Study Comparing Anti-TNFα and Phototherapy.

Background: The risk of developing non-melanoma skin cancers (NMSCs) in patients with psoriasis is highly debated, and, to date, there is no unambiguous consensus opinion. Psoriasis is known to be related to an increased likelihood of other comorbidities such as psoriatic arthritis, obesity, metabolic syndrome, depression, and cardiovascular disease. Regarding cancer risk, previous studies have reported a greater tendency for the development of cutaneous T-lymphomas and colon, breast, kidney, and lung cancers. Furthermore, data from network meta-analyses have shown that patients with psoriasis have a higher risk of developing squamous cell carcinomas (SCCs) and/or basal cell carcinomas (BCCs). Multiple factors may contribute to the development of NMSCs in psoriatic patients, ranging from immunosuppression induced by biologic agents to previous phototherapy. However, the extent to which each factor may impact this risk has not been entirely assessed. The aim of this study was to evaluate the risk of developing NMSCs in patients with psoriasis observed for at least 5 years, by directly comparing patients only treated with phototherapy and patients treated with anti-tumor necrosis factor α (TNFα) agents, naive to other systemic treatments or phototherapy. Methods: We conducted a single-center retrospective study at Siena University Hospital, Italy, on 200 adult patients with psoriasis divided into two groups: (i) group 1, including 100 patients treated with narrow-band UVB phototherapy (nb-UVB), and (ii) group 2, including 100 patients treated with anti-TNFα. The patients included in group 2 had to be naive to cDMARDs and biologics and treated with anti-TNFα continuously for 5 years without loss of efficacy. All patients were observed for 5 years and underwent annual dermatologic examinations to assess for the occurrence of BCC or SCC. Results: A total of 34 out of 100 patients treated with phototherapy had one BCC or one SCC and 10 out of 34 developed two skin cancers. In particular, five had both types (one BCC and one SCC), and five had two BCCs. Conclusions: The results of our study highlight how the risk of developing NMSCs is greater in patients undergoing phototherapy compared to those treated with anti-TNFα. It also draws attention to the consideration that patients with scalp psoriasis might need closer follow-up as they could be more at risk of developing NMSCs.

MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes.

Oxidation processes in mitochondria and different environmental insults contribute to unwarranted accumulation of reactive oxygen species (ROS). These, in turn, rapidly damage intracellular lipids, proteins, and DNA, ultimately causing aging and several human diseases. Cells have developed different and very effective systems to control ROS levels. Among these, removal of excessive amounts is guaranteed by upregulated expression of various antioxidant enzymes, through activation of the NF-E2-Related Factor 2 (NRF2) protein. Here, we show that Mitogen Activated Protein Kinase 15 (MAPK15) controls the transactivating potential of NRF2 and, in turn, the expression of its downstream target genes. Specifically, upon oxidative stress, MAPK15 is necessary to increase NRF2 expression and nuclear translocation, by inducing its activating phosphorylation, ultimately supporting transactivation of cytoprotective antioxidant genes. Lungs are continuously exposed to oxidative damages induced by environmental insults such as air pollutants and cigarette smoke. Interestingly, we demonstrate that MAPK15 is very effective in supporting NRF2-dependent antioxidant transcriptional response to cigarette smoke of epithelial lung cells. Oxidative damage induced by cigarette smoke indeed represents a leading cause of disability and death worldwide by contributing to the pathogenesis of different chronic respiratory diseases and lung cancer. Therefore, the development of novel therapeutic strategies able to modulate cellular responses to oxidative stress would be highly beneficial. Our data contribute to the necessary understanding of the molecular mechanisms behind such responses and identify new potentially actionable targets.

Therapeutic Potential of IL-1 Antagonism in Hidradenitis Suppurativa.

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists.

Psoriasis and Fibromyalgia: A Systematic Review.

Psoriasis is a chronic inflammatory cutaneous condition characterized by several comorbidities, including musculoskeletal disorders. While the association with psoriatic arthritis has been widely addressed in literature, the aim of the present systematic review was to identify all available evidence on the relationship between psoriasis and fibromyalgia, a musculoskeletal syndrome primarily characterized by chronic widespread pain. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and MedLine and Web of Science (WOS) databases were searched for literature up to March 2023. After the removal of duplicate records, a total of 11 articles were deemed eligible for inclusion in a qualitative synthesis. Our results suggested that psoriatic patients had a higher prevalence of fibromyalgia (8-30%), with a very high impact on symptoms of psoriasis. Moreover, fibromyalgic patients had a slightly increased prevalence of psoriasis (2.2-6.7%) compared to the control groups. Finally, several studies demonstrated the substantial impact of fibromyalgia on psoriatic outcome measures in patients with concomitant psoriatic arthritis. In conclusion, available data support a potential interplay between psoriasis and fibromyalgia, but further research is encouraged in this area.

Role of the NLRP1 inflammasome in skin cancer and inflammatory skin diseases.

Inflammasomes are cytoplasmic protein complexes that play a crucial role in protecting the host against pathogenic and sterile stressors by initiating inflammation. Upon activation, these complexes directly regulate the proteolytic processing and activation of proinflammatory cytokines interleukin (IL)-1ß and IL-18 to induce a potent inflammatory response, and induce a programmed form of cell death called pyroptosis to expose intracellular pathogens to the surveillance of the immune system, thus perpetuating inflammation. There are various types of inflammasome complexes, with the NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome being the first one identified and currently recognized as the predominant inflammasome sensor protein in human keratinocytes. Human NLRP1 exhibits a unique domain structure, containing both an N-terminal pyrin (PYD) domain and an effector C-terminal caspase recruitment domain (CARD). It can be activated by diverse stimuli, such as viruses, ultraviolet B radiation and ribotoxic stress responses. Specific mutations in NLRP1 or related genes have been associated with rare monogenic skin disorders, such as multiple self-healing palmoplantar carcinoma; familial keratosis lichenoides chronica; autoinflammation with arthritis and dyskeratosis; and dipeptidyl peptidase 9 deficiency. Recent research breakthroughs have also highlighted the involvement of dysfunctions in the NLRP1 pathway in a handful of seemingly unrelated dermatological conditions. These range from monogenic autoinflammatory diseases to polygenic autoimmune diseases such as vitiligo, psoriasis, atopic dermatitis and skin cancer, including squamous cell carcinoma, melanoma and Kaposi sarcoma. Additionally, emerging evidence implicates NLRP1 in systemic lupus erythematosus, pemphigus vulgaris, Addison disease, Papillon-Lefèvre syndrome and leprosy. The aim of this review is to shed light on the implications of pathological dysregulation of the NLRP1 inflammasome in skin diseases and investigate the potential rationale for targeting this pathway as a future therapeutic approach.

Drug survival of biologics and non-biologics in patients affected by palmoplantar psoriasis: a "real-world", mono-center experience.

BACKGROUND: Data on the treatment of palmoplantar psoriasis (PP) are very limited as these patients are often excluded from clinical trials. Moreover, this form of psoriasis is often resistant to treatment, making its clinical management complex. METHODS: Primary endpoint was to evaluate the clinical and demographic characteristics and the drug survival of both biological and non-biological drugs in a population affected by PP. Secondary endpoint was to highlight any differences between the hyperkeratotic and pustular variant. We analyzed data from 233 psoriasis patients with palmoplantar involvement, with or without chronic plaque psoriasis. We performed a drug-survival analysis with the aid of Kaplan-Meier survival and a multivariate analysis to highlight the influence of certain variables on treatment persistence using a Cox regression model. RESULTS: The drug-survival analysis revealed that biologic drugs compared to non-biologic drugs are associated with a higher persistence in treatment (59.73 vs. 43.56%); in particular, anti-IL23 drugs were found to be the drugs with the best drug-survival overall (67.94% of patients at 60 months are still on these drugs). Furthermore, our multivariate analysis shows that when compared with biological drugs, non-biological drugs are associated with an increased risk of treatment discontinuation (HR = 1.95 [95% CI: 1.41-2.68], P = 0.001). CONCLUSIONS: Our study confirms the difficulty of treating PP and shows that biologic drugs are associated with longer persistence in treatment than non-biologics in both PP's variants, not because of their higher effectiveness but because of their better safety profile.

Characteristics of Primary Cutaneous Lymphoma in Italy: A Tertiary Care, Single-Center Study.

Data on primary cutaneous lymphomas (PCLs) patients in the Italian population are limited, and, despite the existence of several treatment options, the management of those patients remains challenging. Our study aimed to investigate the clinical and therapeutic features of PCL patients in a referral center in Italy. We conducted a retrospective study on 100 consecutive PCL patients between January 2017 and December 2022. The mean (SD) age of our cohort was 70.33 (14.14) years. Cutaneous T-cell lymphomas (CTCLs) represented 65% of all cases; the majority were mycosis fungoides (42%), followed by cases of Sezary syndrome (10%) and primary cutaneous anaplastic large cell lymphoma (4%). Cutaneous B-cell lymphomas (CBCLs) accounted for 35 % of PCLs, with 15 cases of primary cutaneous follicle center lymphoma, 10 cases of primary cutaneous diffuse large B-cell lymphoma leg type, and 9 cases of marginal zone B-cell lymphoma. A higher frequency of pruritus (p = 0.008) and higher peripheral blood levels of beta-2 microglobulin (p ≤ 0.001) and lactate dehydrogenase (p = 0.025) were found in CTCLs compared to those of CBCLs. Considering all therapeutic lines performed, treatments were extremely heterogeneous and skin-directed therapies represented the most frequently used approach. Our study confirms the distribution of PCL subtypes formerly reported in the literature and highlights the utility of real-life data in treatments to improve the current management of PCL patients.