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1.
Acta Derm Venereol ; 104: adv35215, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38567914

ABSTRACT

Phototherapy is an efficient therapy for a variety of skin diseases. Various drugs can cause photosensitivity and impact tolerability of phototherapy. The tolerability was investigated of narrowband ultraviolet-B 311 nm therapy in dependence on the underlying disease and long-term co-medication. A total of 534 narrowband ultraviolet-B therapy courses were examined. Compared with psoriasis, adverse events were observed more frequently in eczematous diseases and, in some cases, other indications. About two-thirds of all courses were carried out in patients taking at least one photosensitising drug, according to the summaries of product characteristics. Phototherapy was more frequently associated with adverse events when medication was taken concomitantly. When considering the tolerability of phototherapy in dependence on individual substances or drug classes, no statistically significant result was shown after adjustment.


Subject(s)
Photosensitivity Disorders , Psoriasis , Ultraviolet Therapy , Humans , Ultraviolet Therapy/adverse effects , Phototherapy , Psoriasis/therapy , Psoriasis/drug therapy , Treatment Outcome
2.
Dtsch Arztebl Int ; (Forthcoming)2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38657176

ABSTRACT

BACKGROUND: Psoriasis was long regarded as an inflammatory disease limited to the skin. Data from dermatologic, rheumatologic and cardiologic research now show it to be a systemic disease, for which the term psoriatic disease is used. METHODS: This paper is based on a selective literature search with special attention to the findings of clinical trials and other current publications, as well as the recommendations of international guidelines. RESULTS: Immunologically mediated inflammation of the skin, arteries, bones, and joints is a central feature of psoriatic disease. Other diseases that are known to be associated with psoriatic disease include hypertension, metabolic syndrome, and depression. The main risk factor for the development of psoriatic disease is obesity, which also increases the likelihood of psoriatic arthritis. The main known trigger factors are stress, infection, and, less commonly, medication. Psoriatic disease is characterized by complex genetics and by a characteristic pattern of inflammation that involves elements of both innate and acquired immunity and, in particular, the cytokines interleukin 17 and 23. The inflammatory processes underlying psoriatic disease can now be targeted with modern biologic and other therapies. CONCLUSION: In view of the complexity of psoriatic disease, structured management is now recommended so that physicians and patients can work together to determine the optimal treatment strategy.

3.
Allergy ; 79(6): 1573-1583, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38641894

ABSTRACT

BACKGROUND: The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD. METHODS: Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release in vivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI. RESULTS: RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. In vivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI. CONCLUSIONS: Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth.


Subject(s)
Dermatitis, Atopic , Keratinocytes , Ribonucleases , Staphylococcus aureus , Humans , Dermatitis, Atopic/metabolism , Ribonucleases/metabolism , Keratinocytes/metabolism , Inflammation/metabolism , Cells, Cultured
4.
Br J Dermatol ; 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38531691

ABSTRACT

BACKGROUND: Interleukin (IL)-13 is a key driver of inflammation and barrier dysfunction in atopic dermatitis (AD). While there is robust evidence that tralokinumab, a monoclonal antibody neutralizing IL-13, reduces inflammation and clinical disease activity, less is known about its effects on barrier function. OBJECTIVES: To characterize effects of tralokinumab treatment on skin barrier function. METHODS: Transepidermal water loss (TEWL), stratum corneum hydration (SCH), natural moisturizing factor (NMF) content, histopathological characteristics, biomarker expression and microbiome composition were evaluated in lesional, non-lesional, and sodium lauryl sulfate (SLS)-irritated skin of 16 AD patients over the course of 16 weeks of tralokinumab treatment. RESULTS: All clinical severity scores decreased significantly over time. At week 16, mean TEWL in target lesions decreased by 32.66% (p = 0.01), and SCH increased by 58.44% (p = 0.004), along with histological reduction in spongiosis (p = 0.003), keratin 16 expression and epidermal thickness (p = 0.001). In parallel, there was a significant decrease in several barrier dysfunction-associated and pro-inflammatory proteins such as fibronectin (p = 0.006), CCL17/TARC (p = 0.025) and IL-8 (p = 0.014), with significant changes already at week 8. Total bacterial load and Staphylococcus aureus abundance were significantly reduced from week 2. CONCLUSION: Tralokinumab treatment improves skin physiology, epidermal pathology, and dysbiosis, further highlighting the pleiotropic role of IL-13 in AD pathogenesis.

5.
Dermatol Ther (Heidelb) ; 14(3): 793-804, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38361013

ABSTRACT

INTRODUCTION: Plaque psoriasis is a chronic relapsing inflammatory skin disease that is associated with extensive disease burden that often requires long-term therapy. Treatment of psoriasis with 4 weeks of the aerosol foam formulation of calcipotriol/betamethasone dipropionate (Cal/BD; Enstilar®, LEO Pharma) has been demonstrated to be effective, well tolerated, and associated with high patient satisfaction. Cal/BD foam is approved as a first-line treatment in multiple countries, where several non-interventional studies (NIS) have corroborated the beneficial efficacy and safety profiles determined in the randomized clinical trials. Heterogenicity in these NIS, however, prevents the use of a data pooling strategy for comparisons of effectiveness outcomes across different patient populations. METHODS: Therefore, here, we report on a post hoc analysis of effectiveness data consolidated from six prospective NIS to discern any differences in improvement in signs and symptoms of psoriasis attributable to Cal/BD foam treatment across the countries. In addition, we provide real-world experience of clinicians with Cal/BD foam treatment, factoring in changes in usage since these NIS were performed in their local markets. RESULTS: This post hoc analysis of Cal/BD foam NIS brings together data outside of randomized clinical trials from six countries to provide real-world evidence in 1388 patients showing that 4 weeks of Cal/BD foam is an effective and safe treatment option with quick onset of action for patients with psoriasis. CONCLUSION: These results show that regardless of NIS location, Cal/BD foam remains a well-tolerated, efficacious option for patient care that could be used as a first-line topical therapy for mild-to-severe psoriasis.

6.
N Engl J Med ; 390(6): 510-521, 2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38324484

ABSTRACT

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).


Subject(s)
Antibodies, Monoclonal , Psoriasis , Receptors, Interleukin , Humans , Double-Blind Method , Interleukin-23/immunology , Peptides/administration & dosage , Peptides/adverse effects , Peptides/therapeutic use , Psoriasis/drug therapy , Psoriasis/immunology , Severity of Illness Index , Treatment Outcome , Receptors, Interleukin/antagonists & inhibitors , Administration, Oral , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Dose-Response Relationship, Drug
9.
Br J Dermatol ; 2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38133615

ABSTRACT

BACKGROUND: The anti-interleukin-23 antibody guselkumab demonstrated favourable Week 24 efficacy and safety over fumaric acid esters (FAE) in systemic-treatment naïve patients with moderate-to-severe plaque psoriasis (study part I). OBJECTIVES: Part II: compare a) sustainability of treatment responses (Weeks 24-32) in guselkumab- and FAE-treated patients and b) treatment responses (Weeks 32-56) in patients treated with guselkumab, FAE, and FAE non-responders switching to guselkumab. Part III: investigate the maintenance of response through Week 100 in patients withdrawn from guselkumab at Week 56. METHODS: At Week 0, systemic-treatment naïve patients were randomised 1:1 to guselkumab (GUS) or FAE as per label. At Week 32, patients with PASI75 response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas non-responders (nr) received guselkumab (FAEnr-GUS; GUSnr-GUS). Guselkumab-treated patients with Week 56 PASI90 response were withdrawn (w) and followed until loss of response or Week 100. RESULTS: At Week 32, 98.2% (54/55) of guselkumab- and 41.2% (14/34) of FAE-treated patients were PASI75 responders. At Week 56, 90.7%, 50.0% and 80.0% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI90 response; 72.2%, 28.6% and 45.0%, respectively, achieved a DLQI score 0/1. At Week 100, 44 weeks post-withdrawal, 47.2% (17/36) and 25.0% (3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained PASI score ≤5. Overall, the adverse event and discontinuation rates were lower for guselkumab than FAE. CONCLUSIONS: In these exploratory analyses, guselkumab, as a first-line systemic treatment or second-line systemic treatment in FAE non-responders, was associated with long-term clinical efficacy up to Week 100, including a withdrawal period.

11.
Front Immunol ; 14: 1212551, 2023.
Article in English | MEDLINE | ID: mdl-38022583

ABSTRACT

Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions.


Subject(s)
Gastrointestinal Microbiome , Pemphigoid, Bullous , Humans , Aged , Gastrointestinal Microbiome/physiology , RNA, Ribosomal, 16S/genetics , Disease Susceptibility , Pilot Projects , gamma-Aminobutyric Acid
12.
medRxiv ; 2023 Oct 05.
Article in English | MEDLINE | ID: mdl-37873414

ABSTRACT

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

13.
Nat Genet ; 55(11): 1892-1900, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37884686

ABSTRACT

Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from 111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations. The mutation rate of keratinocytes was similarly only modestly affected by the disease. We found evidence of positive selection in previously reported driver genes NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and also identified mutations in four genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1) that we hypothesize are selected for in squamous epithelium irrespective of disease status. Finally, we describe a mutational signature of psoralens-a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis.


Subject(s)
Furocoumarins , Psoriasis , Humans , Ficusin/therapeutic use , PUVA Therapy , Psoriasis/drug therapy , Psoriasis/genetics , Psoriasis/pathology , Furocoumarins/therapeutic use , Mutation
14.
J Dtsch Dermatol Ges ; 21(10): 1095-1096, 2023 10.
Article in German | MEDLINE | ID: mdl-37845059
15.
Br J Dermatol ; 189(4): 381-391, 2023 09 15.
Article in English | MEDLINE | ID: mdl-37697683

ABSTRACT

BACKGROUND: Monoclonal antibodies to interleukin (IL)-17 have shown strong efficacy in patients with psoriasis. Izokibep is a unique IL-17A inhibitor with a small molecular size and favourable distribution to sites of inflammation. OBJECTIVES: To evaluate the dose response, efficacy and safety of izokibep in patients with plaque psoriasis. METHODS: In this double-blind, randomized, phase II dose-finding study (AFFIRM-35) in adults with moderate-to-severe plaque psoriasis and inadequate response to two or more standard therapies, patients were randomized (1:1:1:1:1) to placebo or izokibep 2, 20, 80 or 160 mg every 2 weeks for 12 weeks. During the remainder of the 52-week core study, patients given placebo were switched to izokibep 80 mg, and dosing intervals were adapted based on Psoriasis Area and Severity Index (PASI) scores for all patients. The core study was followed by two optional consecutive 1-year extension periods for a total duration of 3 years. The primary endpoint was a 90% reduction in PASI score (PASI 90) at week 12. Additional efficacy outcomes and adverse event (AE) rates were evaluated. RESULTS: In total, 109 patients were randomized [safety set, n = 108 (one exclusion criteria failure); full analysis set, n = 106]. At week 12, PASI 90 response rates were 0%, 5%, 19%, 71% and 59% for the placebo, 2-, 20-, 80- and 160-mg izokibep groups, respectively. Rapid dose-dependent improvements were also observed across other efficacy outcomes. During the placebo-controlled period, AEs in the izokibep groups were similar to placebo except for mild injection site reactions. AEs were generally mild to moderate and the drug was well tolerated. Izokibep maintained efficacy at the higher dosage groups for up to 3 years, with no new safety signals. CONCLUSIONS: Data from this phase II study indicate that izokibep is well tolerated and efficacious in the treatment of plaque psoriasis. Higher doses or more frequent dosing could be explored to further enhance response rates.


Subject(s)
Antibodies, Monoclonal , Psoriasis , Adult , Humans , Antibodies, Monoclonal/adverse effects , Double-Blind Method , Long-Term Care , Psoriasis/drug therapy , Inflammation
17.
Acta Derm Venereol ; 103: adv5671, 2023 May 29.
Article in English | MEDLINE | ID: mdl-37246806

ABSTRACT

Several small studies have indicated that daily emollient use from birth might delay, suppress or prevent atopic dermatitis (AD). Two larger trials did not confirm this; however, a recent smaller study indicated a protective effect if daily emollient use is used in the first 2 months of life. Further research is needed to evaluate the effect of emollient use on development of AD. The current study randomly assigned 50 newborns who were at high risk of developing AD (1:1) to receive general infant skin-care advice (control group), or skin-care advice plus emollient with advice to apply emollient at least once daily until 1 year of age (intervention group). Repeated skin examinations, skin physiology measurements and skin microbiome profiling were performed. Of the children in the intervention and control groups, 28% and 24%, respectively, developed AD (adjusted Relative Risk (RR) 1.19, p = 0.65, adjusted risk difference 0.05). Skin pH decreased and transepidermal water loss and stratum corneum hydration increased over time in both groups with no significant differences. In the intervention group skin microbiome alpha diversity increased earlier, and the abundance of Streptococcus and Staphylococcus species were significantly reduced at month 1. Daily early emollient use in children with high risk of AD was safe, but it did not significantly reduce the risk of developing AD or impact skin physiology development.


Subject(s)
Dermatitis, Atopic , Emollients , Child , Humans , Infant , Infant, Newborn , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/prevention & control , Emollients/adverse effects , Pilot Projects , Skin , Skin Physiological Phenomena , Treatment Outcome
18.
Dermatologie (Heidelb) ; 74(5): 350-355, 2023 May.
Article in German | MEDLINE | ID: mdl-36811642

ABSTRACT

It has long been known that chronic inflammatory systemic diseases, such as psoriasis, pose a high risk of developing comorbidities. In everyday clinical practice, it is therefore of particular importance to identify patients who have an individually increased risk profile. In patients with psoriasis, the comorbidity patterns "metabolic syndrome", "cardiovascular comorbidity" and "mental illness" were identified as particularly relevant in epidemiological studies depending on the duration and severity of the disease. In the everyday care of patients with psoriasis in dermatological practice, the use of an interdisciplinary checklist for risk analysis and the initiation of professional follow-up care has proven valuable. On the basis of an existing checklist, the contents were critically evaluated by an interdisciplinary group of experts and a guideline-oriented update was prepared. In the opinion of the authors, the new analysis sheet represents a practicable, factually focused and updated tool for comorbidity risk assessment in patients with moderate and severe psoriasis.


Subject(s)
Mental Disorders , Metabolic Syndrome , Psoriasis , Humans , Adult , Comorbidity , Psoriasis/complications , Metabolic Syndrome/diagnosis , Risk Assessment , Mental Disorders/epidemiology , Chronic Disease
19.
BMJ Open ; 13(2): e060536, 2023 02 15.
Article in English | MEDLINE | ID: mdl-36792337

ABSTRACT

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease that negatively impacts the quality of life of patients and their families. However, the most commonly used decision-making tools in psoriasis, Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA) and Dermatology Life Quality Index (DLQI), do not fully capture the impact of psoriasis on patients' lives. In contrast, the well-established 5-item WHO Well-being Index (WHO-5) assesses the subjective psychological well-being of patients. Moreover, while drug innovations became available for psoriasis, data on the impact of these therapies on patients' lives and their closest environment (family, physicians) are limited. This study will assess the effect of tildrakizumab, an interleukin-23p19 inhibitor, on the overall well-being of patients with moderate-to-severe psoriasis. Moreover, the long-term benefit of tildrakizumab on physicians' satisfaction and partners' lives of patients with psoriasis will be evaluated. METHODS AND ANALYSIS: This non-interventional, prospective, observational, real-world evidence study will involve multiple sites in Europe and approximately 500 adults with moderate-to-severe psoriasis treated with tildrakizumab. Each patient will be followed for 24 months. The primary endpoint is well-being measured by the WHO-5 questionnaire. Key secondary endpoints include Physician's Satisfaction and partner's quality of life (FamilyPso). Other endpoints will evaluate skin-generic quality of life (DLQI-R), Treatment Satisfaction Questionnaire for Medication (TSQM-9), Treatment-related Patient Benefit Index 'Standard', 10 items (PBI-S-10) and work productivity and activity impairment due to psoriasis (WPAI:PSO). Statistical analyses will be based on observed cases. Multiple imputations will be performed as a sensitivity analysis, and adverse events will be reported. ETHICS AND DISSEMINATION: The study will be conducted according to the protocol, which received ethics committee approval and applicable regulatory requirements of each participating country. The results will be disseminated through scientific publications and congress presentations. TRAIL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04823247 (Pre-results).


Subject(s)
Psoriasis , Quality of Life , Adult , Humans , Chronic Disease , Observational Studies as Topic , Patient Reported Outcome Measures , Prospective Studies , Psoriasis/drug therapy , Severity of Illness Index , Treatment Outcome , Clinical Trials, Phase IV as Topic
20.
Int J Mol Sci ; 24(2)2023 Jan 09.
Article in English | MEDLINE | ID: mdl-36674793

ABSTRACT

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients' age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies.


Subject(s)
Psoriasis , Humans , Psoriasis/metabolism , Skin/metabolism , Interleukins/metabolism , Thalidomide/pharmacology , Thalidomide/therapeutic use
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