Infections in the era of immunobiologicals.

Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios.

Identification of gene signatures and molecular mechanisms underlying the mutual exclusion between psoriasis and leprosy.

Leprosy and psoriasis rarely coexist, the specific molecular mechanisms underlying their mutual exclusion have not been extensively investigated. This study aimed to reveal the underlying mechanism responsible for the mutual exclusion between psoriasis and leprosy. We obtained leprosy and psoriasis data from ArrayExpress and GEO database. Differential expression analysis was conducted separately on the leprosy and psoriasis using DEseq2. Differentially expressed genes (DEGs) with opposite expression patterns in psoriasis and leprosy were identified, which could potentially involve in their mutual exclusion. Enrichment analysis was performed on these candidate mutually exclusive genes, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The expression of these hub genes was further validated in an external dataset to obtain the critical mutually exclusive genes. Additionally, immune cell infiltration in psoriasis and leprosy was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between critical mutually exclusive genes and immune cells was also examined. Finally, the expression pattern of critical mutually exclusive genes was evaluated in a single-cell transcriptome dataset. We identified 1098 DEGs in the leprosy dataset and 3839 DEGs in the psoriasis dataset. 48 candidate mutually exclusive genes were identified by taking the intersection. Enrichment analysis revealed that these genes were involved in cholesterol metabolism pathways. Through PPI network analysis, we identified APOE, CYP27A1, FADS1, and SOAT1 as hub genes. APOE, CYP27A1, and SOAT1 were subsequently validated as critical mutually exclusive genes on both internal and external datasets. Analysis of immune cell infiltration indicated higher abundance of 16 immune cell types in psoriasis and leprosy compared to normal controls. The abundance of 6 immune cell types in psoriasis and leprosy positively correlated with the expression levels of APOE and CYP27A1. Single-cell data analysis demonstrated that critical mutually exclusive genes were predominantly expressed in Schwann cells and fibroblasts. This study identified APOE, CYP27A1, and SOAT1 as critical mutually exclusive genes. Cholesterol metabolism pathway illustrated the possible mechanism of the inverse association of psoriasis and leprosy. The findings of this study provide a basis for identifying mechanisms and therapeutic targets for psoriasis.

Janus-kinase inhibitors in dermatology: A review of their use in psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease.

Recent studies on molecular pathways have elucidated novel therapeutic approaches in inflammatory and autoimmune skin disorders. Specifically, the dysregulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) cascade plays a central role in the pathogenesis of many skin conditions. JAK inhibitors, with their ability to selectively target immune responses, are potential treatment options. Using the National Library of Medicine, we provide a comprehensive review of the use of United States Food and Drug Administration (FDA)-approved and emerging JAK or tyrosine kinase 2 (TYK2) inhibitors in a wide range of dermatologic conditions, including psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. In patients with psoriasis, oral deucravacitinib (TYK2 inhibitor) has been approved as a once-daily therapy with demonstrated superiority and efficacy over apremilast and placebo and tolerable safety profiles. In patients with vitiligo, topical ruxolitinib (JAK1 inhibitor) is approved as a twice-daily treatment for repigmentation. The efficacy of several other JAK inhibitors has also been demonstrated in several clinical trials and case studies for systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. Further investigations with long-term clinical trials are necessary to confirm their utility in treatment and safety for these diseases.

Preparation and characterization of solid lipid nanoparticles encapsulated noscapine and evaluation of its protective effects against imiquimod-induced psoriasis-like skin lesions.

Psoriasis is a chronic inflammatory skin disease characterized by thickening the epidermis with erythema, scaling, and proliferation. Noscapine (NOS) has several anti-inflammatory, anti-angiogenic, and anti-fibrotic effects, but its low solubility and large size results in its lower efficacy in the clinic. In this regard, solid lipid nanoparticles (SLN) encapsulated NOS (SLN-NOS) were fabricated using the well-known response surface method based on the central composite design and modified high-shear homogenization and ultrasound method. As a result, Precirol® was selected as the best lipid base for the SLN formulation based on Hildebrand-Hansen solubility parameters, in which SLN-NOS 1 % had the best zeta potential (-35.74 ± 2.59 mV), average particle size (245.66 ± 17 nm), polydispersity index (PDI, 0.226 ± 0.09), high entrapment efficiency (89.77 %), and ICH-based stability results. After 72 h, the SLN-NOS 1 % released 83.23 % and 58.49 % of the NOS at pH 5.8 and 7.4, respectively. Moreover, Franz diffusion cell's results indicated that the skin levels of NOS for SLN and cream formulations were 46.88 % and 13.5 % of the total amount, respectively. Our pharmacological assessments revealed that treatment with SLN-NOS 1 % significantly attenuated clinical parameters, namely ear thickness, length, and psoriasis area and severity index, compared to the IMQ group. Interestingly, SLN-NOS 1 % reduced the levels of interleukin (IL)-17, tumor necrosis factor-α, and transforming growth factor-ß, while elevating IL-10, compared to the IMQ group. Histology studies also showed that topical application of SLN-NOS 1 % significantly decreased parakeratosis, hyperkeratosis, acanthosis, and inflammation compared to the IMQ group. Taken together, SLN-NOS 1 % showed a high potential to attenuate skin inflammation.

Pustular psoriasis: A distinct aetiopathogenic and clinical entity.

Pustular psoriasis is a distinct subset of psoriasis that presents with involvement of the skin in the form of sterile pustules along with systemic manifestations. Though it has been conventionally grouped under the umbrella of psoriasis, recent research has shed light on its pathogenetic mechanisms associated with the IL-36 pathway, which is distinct from conventional psoriasis. Pustular psoriasis in itself is a heterogeneous entity consisting of various subtypes, including generalised, localised, acute, and chronic forms. There is confusion regarding its current classification as entities like deficiency of IL-36 antagonist (DITRA) which are closely related to pustular psoriasis both in their pathogenetic mechanism and its clinical manifestations, are not included under pustular psoriasis. Entities like palmoplantar pustulosis, which presents with similar clinical features but is pathogenetically distinct from other forms of pustular psoriasis, are included under this condition. Management of pustular psoriasis depends upon its severity; while some of the localised variants can be managed with topical therapy alone, the generalised variants like Von Zumbusch disease and impetigo herpetiformis may need intensive care unit admission and tailor-made treatment protocols. The advent of newer biologics and better insight into the pathogenesis of pustular psoriasis has opened the way for newer therapies, including tumour necrosis factor-alpha inhibitors, interleukin-1 inhibitors, interleukin-17 inhibitors, and granulocyte monocyte apheresis. It continues to be an enigma whether pustular psoriasis is actually a variant of psoriasis or an entirely different disease entity, though we feel that it is an entirely different disease process.

Review of the reasons for and effectiveness of switching biologics for psoriasis treatment in Korea.

Background Switching of biologics in patients has become common in clinical practice. Objectives This study investigated the reasons for and effectiveness of switching biologic agents during the treatment of psoriasis. Methods We retrospectively reviewed patients with psoriasis who were treated with biologics at Pusan National University Hospital and Chosun University Hospital from March 2012 to June 2020. We assessed their demographics and treatment characteristics (reasons for switching biologics and efficacy of the first- and second biologic agents). Results Of the 162 psoriatic patients treated with biologic agents for more than 52 weeks, 35 required a switch to another biologic agent. The reasons for switching biologic agents were inefficacy (n = 30), adverse events (n = 2) and others (n = 3). The mean psoriasis area and severity index (PASI) score was 12.1 at the start of the second biologic and 3.4 at 14-16 weeks later. Patients were more likely to switch to another biologic agent when they exhibited a high initial psoriasis area and severity index score and concomitant psoriatic arthritis. Limitations As a retrospective study, there were some limitations such as lack of a placebo control group and the time point of 14-16 weeks being somewhat early to judge the effect of the biologics. Conclusions The most common reason for switching biologic agents in Korea was treatment inefficacy, especially secondary failure. Despite the inefficacy of previous biologic agents, switching to a different agent may be an efficacious approach.

Enthesopathy in patients with nail psoriasis - a cross-sectional evaluation of clinical, onychoscopic and ultrasonographic features.

Background Nail involvement in psoriasis is common and may be an indicator not only of disease severity, but also of the presence of psoriatic arthritis. However, the relationship of nail psoriasis with enthesitis remains under-explored. Aims This study was conducted to evaluate the clinical, onychoscopic (nail dermatoscopic) and ultrasonographic features in patients with nail psoriasis. Materials and Methods All nails of twenty adult patients with nail psoriasis were examined clinically and onychoscopically. Patients were evaluated for psoriatic arthritis (Classification Criteria for Psoriatic Arthritis), the severity of cutaneous disease (Psoriasis Area Severity Index) and nail disease (Nail Psoriasis Severity Index). Ultrasonography of the clinically involved digits was performed for evidence of distal interphalangeal joint enthesitis. Results Out of 20 patients, 18 patients had cutaneous psoriasis and 2 had isolated nail involvement. Among the 18 patients with skin psoriasis, 4 had associated psoriatic arthritis. The most commonly observed clinical and onychoscopic features were pitting (31.2% and 42.2%), onycholysis (36% and 36.5%) and subungual hyperkeratosis (30.2% and 30.5%), respectively. Ultrasonographic evidence of distal interphalangeal joint enthesitis was seen in 57% (175/307) of the digits with clinical nail involvement. Enthesitis was more common in patients with psoriatic arthritis (77% vs 50.6%). Nail thickening, crumbling and onychorrhexis (all features of nail matrix involvement) were significantly associated with enthesitis (P < 0.005). Limitation The major limitation was the small sample size and lack of controls. Only the clinically involved digits were evaluated for enthesitis. Conclusion Enthesitis was frequently detected on ultrasonography in patients with nail psoriasis, even in clinically asymptomatic individuals. Nail features of thickening, crumbling and onychorrhexis may predict underlying enthesitis and the potential development of arthritis. A comprehensive evaluation could help identify patients with psoriasis at risk for arthritis, helping improve long-term outcomes.

The role of glucose-dependent insulinotropic polypeptide 3 (G1P-3) and nucleolar phosphoprotein-1 (NPM1) in pathogenesis of psoriasis.

Background Psoriasis is a multifactorial, hyperproliferative, chronic inflammatory skin disease affecting males and females equally. Aims To study the expression of certain non-coding RNAs, Interferon Alpha Inducible Protein 6 (IFI6), previously named Glucose-dependent Insulinotropic Polypeptide 3 (G1P-3), and nucleolar phosphoprotein (in serum and tissue), and to attempt to elucidate their role in the pathogenesis of psoriasis, which in turn might help in treatment. Methods Twenty patients with psoriasis and 20 healthy subjects were included in this study. Serum and skin biopsies were obtained from all participants. Molecular biology techniques were employed to estimate the expression levels of long noncoding G1P-3 and nucleolar phosphoprotein in serum and skin biopsy. Results Psoriasis patients had a mean age of 41.85 ± 12.29. The median serum G1P-3 level of the patients' group (3.330) was significantly higher than that of the control group (1.085) (P ≤ 0.001). Tissue G1P-3 level of the patients' group (6.495) was also significantly higher compared to that of controls (1.040) (P ≤ 0.001). Similarly, for nucleolar phosphoprotein, the median serum level of patients' group (2.030) was significantly higher than that of controls (1.040) (P ≤ 0.001) and median tissue level (5.425) was also significantly higher than that of controls (1.040) (P ≤ 0.001). Limitations In this study, only outpatients were included and follow-up was not well-handled. For future work, follow-up can be considered. Conclusion Long non-coding G1P-3 as well as nucleolar phosphoprotein may be considered as genetic markers for psoriasis susceptibility. In future, these might provide a novel direction for advances in psoriasis treatment.

Methotrexate monotherapy versus methotrexate and apremilast combination therapy in the treatment of palmoplantar psoriasis: A prospective, randomised, assessor-blinded, comparative study.

BACKGROUND: Palmoplantar psoriasis is a chronic debilitating condition which significantly impairs quality of life. OBJECTIVES: To assess the efficacy and safety of the combination of apremilast and methotrexate compared with methotrexate monotherapy in the treatment of palmoplantar psoriasis. Also, to study the impact on treatment on the Dermatology Life Quality Index and Palmoplantar Quality of Life Index. METHODS: A total of 64 patients were randomised to two groups in a 1:1 ratio - Group A received both methotrexate and apremilast in combination, while Group B received only methotrexate, for 16 weeks. The primary endpoints were the mean score of Modified Palmoplantar Psoriasis Area and Severity Index at week 16, the proportion of patients achieving modified palmoplantar psoriasis area severity index-75 and/or Palmoplantar Psoriasis Physician Global Assessment score 0/1 at week 16. RESULTS: A significantly higher proportion of patients in Group A achieved Modified Palmoplantar Psoriasis Area and Severity Index-75 at week 16 (43% in Group A vs 30% in Group B). The Modified Palmoplantar Psoriasis Area and Severity Index score was significantly lower in the combination group at week 16 (4.03 ± 2.05 in Group A and 5.89 ± 2.31 in Group B, P-value = 0.002). About 80% of patients in the combination group with baseline Palmoplantar Psoriasis Physician Global Assessment ≥3 achieved Palmoplantar Psoriasis Physician Global Assessment 0/1 compared to 60% in Group B. The combination group showed a significantly higher reduction in Dermatology Life Quality Index and Palmoplantar Quality of Life Index scores compared to the methotrexate alone group (P-value = 0.025). No notable adverse events were observed. LIMITATION: The limitations of the study were single blinding, small sample size and a lack of longer follow up to assess the rate of relapse. We did not account for attrition during sample size calculation. Also, due to the paucity of data regarding the use of apremilast in palmoplantar psoriasis, definitive comparisons could not be made with previous studies. CONCLUSION: The combination of apremilast and methotrexate has superior efficacy and a similar safety profile as compared to methotrexate monotherapy for the treatment of moderate to severe palmoplantar psoriasis.

Single-nucleotide polymorphism and haplotype analysis of macrophage migration inhibitory factor gene and its correlation with serum macrophage migration inhibitory factor levels in North Indian psoriatic patients with moderate disease severity: A cross-sectional study.

BACKGROUND: Psoriasis is associated with significant morbidity and impaired quality of life. Identification of the host genes that influence disease susceptibility and can potentially guide future, targeted therapy is the need of the hour. AIMS: The aim of the study was to investigate the associations of macrophage migration inhibitory factor (MIF) gene polymorphisms, that is, a 5-8-CATT tetra nucleotide repeats at -794 (-794*CATT5-8) and a single-nucleotide polymorphism at -173 (-173*G/C) with the risk of chronic plaque psoriasis and to observe the correlation, if any, of disease determinants with genetic functional variants and circulating MIF levels. METHODS: Five hundred and seventeen individuals (265 psoriasis patients and 252 controls) were genotyped for MIF gene polymorphisms. Data were analyzed with respect to disease susceptibility, serum MIF levels, disease severity, age at onset, disease duration and presence of comorbidities. RESULTS: The presence of co-morbidities was more frequently noted in patients with late onset disease (P = 0.01). No statistically significant differences were observed either in genotype (P = 0.680) or allele frequency (P = 0.69) with respect to distribution of MIF-173*G/C polymorphism between patients and controls. The frequencies of genotypes -794*CATT 5/7 and 7/7 were significantly lower in patients (P = 0.027* and 0.038*, respectively). CATT*5/MIF-173*C haplotype occurred at a higher frequency in patients (odds ratio 3.03, 95% confidence intervals 1.09-8.47, P = 0.02). The mean serum MIF levels were significantly higher in patients as compared to controls (P < 0.001). The presence of either extended MIF -794*CATT repeats or C allele did not reveal any significant association with serum MIF levels or age at onset. Analysis of effect of various disease determinants revealed no significant association with genetic variants and serum MIF levels. LIMITATIONS: The lesional expression of MIF could not be studied. CONCLUSION: Our results showed that CATT*5/MIF-173*C haplotype is associated with increased susceptibility to psoriasis vulgaris.

Increased risk of atrial fibrillation in patients with psoriasis: A meta-analysis of observational studies.

BACKGROUND: Several epidemiological studies have shown that psoriasis increases the risk of developing atrial fibrillation but evidence of this is still scarce. AIMS: Our objective was to systematically review, synthesise and critique the epidemiological studies that provided information about the relationship between psoriasis and atrial fibrillation risk. METHODS: We searched through PubMed, EMBASE and the bibliographies for articles published between 1 January 2000, and 1 November 2017, that reported on the association between psoriasis and atrial fibrillation. All abstracts, full-text articles and sources were reviewed with duplicate data excluded. Summary relative risks (RRs) with 95% CI were pooled using a random effects model. RESULTS: We identified 252 articles, of these eight unique abstracts underwent full-text review. We finally selected six out of these eight studies comprising 11,187 atrial fibrillation patients. The overall pooled relative risk (RR) of atrial fibrillation was 1.39 (95% CI: 1.257-1.523, P < 0.0001) with significant heterogeneity (I2 = 80.316, Q = 45.723, τ2 = 0.017, P < 0.0001) for the random effects model. In subgroup analysis, the greater risk was found in studies from North America, RR 1.482 (95% CI: 1.119-1.964, P < 0.05), whereas a moderate risk was observed in studies from Europe RR 1.43 (95% CI: 1.269-1.628, P < 0.0001). LIMITATIONS: We were only able to include six studies with 11,178 atrial fibrillation patients, because only a few such studies have been published. CONCLUSION: Our results showed that psoriasis is significantly associated with an increased risk of developing atrial fibrillation. Therefore, physicians should monitor patient's physical condition on a timely basis.

Case Report: Lepromatous Leprosy and Psoriasis: An Uncommon Coincidence.

Leprosy, a chronic infectious disease, and psoriasis, an inflammatory disorder, are distinct entities. Epidemiology data show that these two diseases are almost mutually exclusive, with only a few reported cases of their coexistence. Here, we present the case of a patient manifesting intermingled psoriatic and leprosy lesions diagnosed as borderline lepromatous leprosy and plaque psoriasis. Of note, Mycobacterium leprae bacilli were detected not only in the two types of lesions but also in normal-appearing skin and blood.

The use of medicinal plants for the treatment of psoriasis: A systematic review and meta-analysis.

Background Psoriasis is a chronic inflammatory disease that presents as scaly patches on the skin that affects about 3% of the world's population. Adherence to treatment and discrimination against people are common problems, adversely impacts quality of life. Objectives The aim of this study was to investigate the use of medicinal plants as therapeutic adjuvants in the treatment of plaque psoriasis through a systematic review and meta-analysis. Methods A systematic review and meta-analysis of randomized controlled trials in patients with plaque psoriasis was carried out, comparing the efficacy of herbal treatments alone or in association with other therapies. The search was performed in the databases of The Cochrane Library, Lilacs, Medline via PubMed and Embase, only including studies published from 2016 to 2020.The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. A systematic review and meta-analysis of randomized controlled trials (RCT) in patients with plaque psoriasis was carried out, comparing the efficacy of herbal treatments alone or in association with other therapies. We comprehensively searched the MEDLINE, Embase, Lilacs and Cochrane Library databases, only including studies published from 2016 to 2020. The certainty of evidence was assessed using the GRADE approach. Results Out of 2,268 articles evaluated, only seven RCT were eligible for final analysis. Five of these studies evidenced low risk of bias and a high level of evidence. Limitations Few RCT of medicinal plants. Conclusion This meta-analysis indicates that medicinal plants may be used as topical or oral products, either alone or combined with other forms of treatment. These products have the potential to greatly improve the quality of life of the patient.

Total oxidant capacity, total antioxidant capacity, ischemic modified albumin, microRNA levels, and their relationship with psoriasis area and severity index.

Aims To examine the differences in the levels of microRNA, ischemic modified albumin (IMA), total oxidant capacity (TOC), and total antioxidant capacity (TAC) of persons with and without psoriasis and, in the case group, the relationship between these parameters and psoriasis area and severity index (PASI). Methods Blood samples were collected from patients and healthy participants to examine levels of these parameters. Results The mean serum TOC level was higher in the case group. The mean serum TAC and IMA levels were significantly lower in the case group (P <0.001). It was observed that the mean serum miR-203 and miR-146a levels were increased in psoriasis patients. It was determined that there was only a significant positive weak correlation between miR-203 and PASI (r = 0.232, P = 0.027). Limitations The small sample size, not controlling serum albumin and not evaluating the effects of the treatment agents used by the patients on oxidative and inflammatory processes. Conclusion In the case group changes in the mean serum TOC and TAC levels provide evidence that oxidative stress may play a critical role in disease pathogenesis. The increase in the mean serum miR-203 and miR-146a levels suggest the possibility of therapies targeting these microRNAs as a new option.

Correlation of IL36RN and CARD14 mutations with clinical manifestations and laboratory findings in patients with generalised pustular psoriasis.

Background Generalized pustular psoriasis (GPP) is a chronic disease associated with genetic factors related to mutations of the interleukin 36 receptor antagonist gene (IL36RN) and the caspase recruitment domain 14 gene (CARD14). However, the relevance of these mutations to the clinical features and severity of GPP remains unclear. Aims Our objective was to correlate the presence of IL36RN and CARD14 mutations with the clinical and laboratory findings in patients with GPP. Methods This cross-sectional descriptive study was conducted in 64 subjects with GPP. Clinical manifestations were recorded and the severity was graded as mild, moderate, or severe. Routine laboratory tests were performed and blood samples were collected for Sanger sequencing. The clinical data of patients were compared among the different mutation groups. Results The two main variants of IL36RN were c.115+6T > C (p.Arg10ArgfsX1) and c.227C > T (p.Pro76Leu). The major CARD14 mutations were c.2458C > T (p.Arg820Trp), c.1641C > T (p.Arg547Ser), and c.1753G > A transitions. Provocative factors were uncommon in the group with both IL36RN and CARD14 mutations. Drugs (unspecified), especially herbals, were the most common triggers. A history of psoriasis was frequent in patients with only CARD14 mutations, but fever was uncommon. The c.1641C > T mutation was associated with leukocytosis > 15000/mm3 and the c.1753G > A mutation was associated with hypoalbuminemia <3.8g/dL. Both the c.115+6T > C and c.227C > T variants of IL36RN were associated with fever ≥38.5°C while the c.115+6T > C variant was also associated with geographic tongue. No gene mutations were associated with the total severity and severity grades. Limitations Four patients without the two major IL36RN mutations were excluded from the study. Conclusion The presence of IL36RN and CARD14 mutations were associated with a history of psoriasis, various provocative factors, fever, leukocytosis, hypoalbuminemia, and geographic tongue. Further studies to explore the role of these mutations in therapeutic efficacy and disease outcomes are necessary.