Clinical improvement in psoriasis with specific targeting of interleukin-23

Villanova F., Flutter B., Tosi I., Grys K., Sreeneebus H., Perera G.K., Chapman A., Smith C.H., Di Meglio P., Nestle F.O.

Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte-associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti-tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.

Lowes M.A., Suárez-Fariñas M., Krueger J.G.

The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.

Ngiow S.F., Teng M.W., Smyth M.J.

Interleukin (IL)-12 and IL-23 share the IL-12p40 molecule. IL-12 promotes T helper (Th)1 immunity and IL-23 promotes Th17 immunity, and it has recently become apparent that the balance between IL-12 and IL-23 is important in carcinogenesis. A series of studies demonstrated that, where tumor initiation, growth, and metastasis are concerned, IL-12 may act independently of interferon (IFN)-γ, and IL-23 independently of IL-17A. This review explores the activity of IL-23 in carcinogenesis. In the context of the tumor-inhibitory effects of IL-12, and tumor-promoting effects of IL-23, we discuss the use of anti-IL-12p/23 monoclonal antibodies (mAbs) in autoimmune inflammatory disorders and the alternative specific neutralization of IL-23.

Keijsers R.R., van der Velden H.M., van Erp P.E., de Boer-van Huizen R.T., Joosten I., Koenen H.J., van de Kerkhof P.C.

Papp K.A., Griffiths C.E., Gordon K., Lebwohl M., Szapary P.O., Wasfi Y., Chan D., Hsu M.-., Ho V., Ghislain P.D., Strober B., Reich K.

Krueger J.G., Fretzin S., Suárez-Fariñas M., Haslett P.A., Phipps K.M., Cameron G.S., McColm J., Katcherian A., Cueto I., White T., Banerjee S., Hoffman R.W.

Background In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell–derived cytokines. Evidence suggests that the TH17 cell cytokine IL-17A (IL-17) might play a role in disease pathogenesis. Objective We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects. Methods We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti–IL-17 mAb ixekizumab (previously LY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4. Results There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-α was of higher magnitude at 2 weeks than in prior studies with TNF-α antagonism. Conclusion Our data suggest that IL-17 is a key "driver" cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis.

Torzicky M., Viznerova P., Richter S., Strobl H., Scheinecker C., Foedinger D., Riedl E.

The reverse transmigration (RT) of tissue-resident dendritic cells (DCs) across lymphatic endothelia is prerequisite for the initiation of adaptive immune responses and might be regulated in a manner similar to diapedesis. Specifically, CD31 and CD99, which act as gatekeepers during diapedesis, might have a role in RT of DCs. We found that human lymphatic endothelial cells (LECs) and DCs in vitro and in human skin explants express CD31 and CD99. In human skin, CD31 was enriched along intercellular surfaces of LECs, whereas CD99 was preferentially confined to luminal surfaces as evidenced by immunoelectron microscopy. Confocal microscopy analysis revealed that tumor necrosis factor-alpha (TNF-α) and CXCL12 acted as inducers of RT in vitro, but only CXCL12 stimulation resulted in a significant increase in migration rate of DCs. Upon TNF-α stimulation, CXCL12 mRNA levels transiently increased in human fibroblasts and LECs, whereas CXCL12 protein expression levels did not significantly change. Blocking mAbs to CD31 and CD99 significantly reduced RT of DCs across cultured human LEC monolayers and blocked CXCL12-induced migration of DCs in whole-skin explants. In sum, this study shows that CD31 and CD99 are involved in the RT of DCs across LECs and that similar mechanisms promote both diapedesis and RT.

Langley R.G.

The introduction of the biologic agents, adalimumab, etanercept, infliximab and ustekinumab, has provided more options for the short- and long-term treatment of patients with psoriasis. Physicians are now able to achieve and maintain effective disease control in more patients using biologic therapies. Newly published clinical data support the introduction of novel optimization strategies to further improve outcomes in patients with psoriasis. Recent randomized controlled clinical trials have provided data on the efficacy of conventional therapies, including systemic agents, and biologics at specific time points. Switching from methotrexate to a tumour necrosis factor (TNF)-α antagonist after 16 weeks can improve response rates, as demonstrated in a study of patients with moderate-to-severe psoriasis, while the benefit of long-term methotrexate use remains unclear. In a separate study, psoriasis area and severity index (PASI) ≥ 75 response rates were maintained over time (>3 years for adalimumab), suggesting that long-term biologic therapy is an effective and sustainable treatment option for psoriasis. For each individual patient, the benefit of a particular treatment needs to be balanced with the risks. The lack of head-to-head trials of antipsoriatic therapies, particularly biologic therapies, does not help with making individualized treatment decisions. However, a benefit-risk assessment of TNF-α antagonists calculated from an integrated analysis of published literature in moderate-to-severe psoriasis can be used to aid clinical practice. The number needed to treat, number needed to harm and number of patient years of observation to detect an adverse event have been determined for adalimumab, etanercept and infliximab. The benefit-risk profiles generated demonstrated that, during the initial year of treatment, likelihood of success with TNF-α antagonists was several orders of magnitude greater than the likelihood of serious toxicity.

Bustamante J., Picard C., Boisson-Dupuis S., Abel L., Casanova J.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria, such as Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccines and nontuberculous, environmental mycobacteria (EM). Since 1996, MSMD-causing mutations have been found in six autosomal genes involved in IL-12/23-dependent, IFN-γ-mediated immunity. The aim of this review is to provide the description of the two described forms of X-linked recessive (XR) MSMD. Germline mutations in two genes, NEMO and CYBB, have long been known to cause other human diseases-incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (NEMO/IKKG), and X-linked chronic granulomatous disease (CGD) (CYBB)-but specific mutations in either of these two genes have recently been shown to cause XR-MSMD. NEMO is an essential component of several NF-κB-dependent signaling pathways. The MSMD-causing mutations in NEMO selectively affect the CD40-dependent induction of IL-12 in mononuclear cells. CYBB encodes gp91(phox) , which is an essential component of the NADPH oxidase in phagocytes. The MSMD-causing mutation in CYBB selectively affects the respiratory burst in macrophages. Mutations in NEMO and CYBB may therefore cause MSMD by selectively exerting their deleterious impact on a single signaling pathway (CD40-IL-12, NEMO) or a single cell type (macrophages, CYBB). These experiments of Nature illustrate how specific germline mutations in pleiotropic genes can dissociate signaling pathways or cell lineages, thereby resulting in surprisingly narrow clinical phenotypes.

Bangert C., Strober B.E., Cork M., Ortonne J., Luger T., Bieber T., Ferguson A., Ecker R.C., Kopp T., Weise-Riccardi S., Guettner A., Stingl G.

<i>Background:</i> Topical pimecrolimus may maintain remissions of atopic dermatitis (AD) by inhibiting subclinical inflammation. <i>Objective:</i> To evaluate clinical and cytological effects of pimecrolimus in topical corticosteroid-treated and resolved AD lesions. <i>Methods:</i> Patients (n = 67) with resolved AD lesions were randomized to 3-week double-blind treatment with either pimecrolimus cream 1% or vehicle cream. Outcome measures were reduction in Eczema Area and Severity Index (EASI) and number of leukocytes in skin biopsies in all randomized patients who were evaluable at the end of study. <i>Results:</i> The proportion of patients with a localized EASI <2 at the end of study was higher with pimecrolimus cream 1% than with vehicle cream (73.5 vs. 39.4%, respectively). There was a significant decrease in the number of infiltrating CD45+ cells in pimecrolimus cream 1% compared with placebo cream (–88.2 vs. 43.2 cells/mm², respectively, p = 0.047) and a slight but nonsignificant reduction in the number of dermal dendritic cells, Langerhans cells, T cells and macrophages with pimecrolimus versus vehicle cream. <i>Limitations:</i> This was an exploratory study. <i>Conclusion:</i> Topical pimecrolimus was effective at maintaining betamethasone-17α-valerate-induced AD remission by inhibiting recurrences of the inflammatory infiltrate in the skin.

Hueber W., Patel D.D., Dryja T., Wright A.M., Koroleva I., Bruin G., Antoni C., Draelos Z., Gold M.H., Durez P., Tak P.P., Gomez-Reino J.J., Foster C.S., Kim R.Y., Samson C.M., et. al.

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis.

Wolk K., Witte E., Warszawska K., Schulze-Tanzil G., Witte K., Philipp S., Kunz S., Döcke W., Asadullah K., Volk H., Sterry W., Sabat R.

Psoriasis is a common chronic skin disease. Recent studies demonstrated that IL-20 and IL-22, cytokines produced by keratinocytes and T cells, respectively, both inhibit keratinocyte terminal differentiation and induce psoriasis-like epidermis alterations. Here, we investigated the relationship between these mediators. Although IL-20 was not able to regulate IL-22 production, IL-22 induced IL-20 mRNA and protein in human keratinocytes. However, IL-22 had only a minimal effect, if any, on IL-19 and IL-26. Cutaneous IL-20 was also elevated in mice following IL-22 application. Accordingly, some of IL-22's effects on differentiation-regulating genes were partially mediated by an endogenous, secreted protein and attenuated by anti-IL-20 Ab. Like IL-22, IL-17A and TNF-alpha induced IL-20 in keratinocytes, whereas IFN-gamma and IL-20 itself did not. Furthermore, IL-17A and TNF-alpha individually strengthened the IL-22-induced IL-20 production. In lesional skin of psoriasis patients, highly elevated IL-20 levels strongly correlated with IL-22, and to a lesser extent, with IL-17A and TNF-alpha. As previously shown for IL-22, IL-20 blood levels correlated with the disease severity, although with a lower significance. This study demonstrates that a T-cell mediator induces a tissue cell mediator with similar effects to its own and therefore suggests the existence of a novel type of pathogenetic cascade.

Guttman-Yassky E., Lowes M.A., Fuentes-Duculan J., Zaba L.C., Cardinale I., Nograles K.E., Khatcherian A., Novitskaya I., Carucci J.A., Bergman R., Krueger J.G.

Abstract The classical Th1/Th2 paradigm previously defining atopic dermatitis (AD) and psoriasis has recently been challenged with the discovery of Th17 T cells that synthesize IL-17 and IL-22. Although it is becoming evident that many Th1 diseases including psoriasis have a strong IL-17 signal, the importance of Th17 T cells in AD is still unclear. We examined and compared skin biopsies from AD and psoriasis patients by gene microarray, RT-PCR, immunohistochemistry, and immunofluorescence. We found a reduced genomic expression of IL-23, IL-17, and IFN-γ in AD compared with psoriasis. To define the effects of IL-17 and IL-22 on keratinocytes, we performed gene array studies with cytokine-treated keratinocytes. We found lipocalin 2 and numerous other innate defense genes to be selectively induced in keratinocytes by IL-17. IFN-γ had no effect on antimicrobial gene-expression in keratinocytes. In AD skin lesions, protein and mRNA expression of lipocalin 2 and other innate defense genes (hBD2, elafin, LL37) were reduced compared with psoriasis. Although AD has been framed by the Th1/Th2 paradigm as a Th2 polar disease, we present evidence that the IL-23/Th17 axis is largely absent, perhaps accounting for recurrent skin infections in this disease.

Skvara H., Dawid M., Kleyn E., Wolff B., Meingassner J.G., Knight H., Dumortier T., Kopp T., Fallahi N., Stary G., Burkhart C., Grenet O., Wagner J., Hijazi Y., Morris R.E., et. al.

PKC isoforms tau, alpha, and beta play fundamental roles in the activation of T cells and other immune cell functions. Here we show that the PKC inhibitor AEB071 both abolishes the production of several cytokines by activated human T cells, keratinocytes, and macrophages in vitro and inhibits an acute allergic contact dermatitis response in rats. To translate these findings into humans, single and multiple ascending oral doses of AEB071 were administered to healthy volunteers and patients with psoriasis, respectively. AEB071 was well tolerated with no clinically relevant laboratory abnormalities. Ex vivo stimulation of lymphocytes from subjects exposed to single doses of AEB071 resulted in a dose-dependent inhibition of both lymphocyte proliferation and IL2 mRNA expression. Clinical severity of psoriasis was reduced up to 69% compared with baseline after 2 weeks of treatment, as measured by the Psoriasis Area Severity Index (PASI) score. The improvement in psoriasis patients was accompanied by histological improvement of skin lesions and may be partially explained by a substantial reduction of p40+ dermal cells, which are known to mediate psoriasis. These data suggest that AEB071 could be an effective novel treatment regimen for psoriasis and other autoimmune diseases, and that AEB071 warrants long-term studies to establish safety and efficacy.

Papp K.A., Langley R.G., Lebwohl M., Krueger G.G., Szapary P., Yeilding N., Guzzo C., Hsu M., Wang Y., Li S., Dooley L.T., Reich K.

Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but

Luo L., Ji J., Dong J., He M., Jiang W., Liu Y., Wang W.

CD3 + CD20 + T cells (TB cells) are a subset of lymphocytes in the human body that are associated with inflammation. They originate from T cells interacting with B cells, and their levels are abnormally elevated in individuals with immune disorders, as well as in some cancer patients. The interplay between tumor immunity and inflammation is intricate, yet the specific involvement of TB cells in local tumor immunity remains uncertain, with limited research on their subtypes. Lung cancer surgical samples were stained using multi-color immunofluorescence to study the subtypes and distribution patterns of TB cells. TB cells were confirmed to exist in a scattered pattern within tertiary lymphoid structures (TLS) in lung cancer tissues, with higher abundance in mature TLS. In subtype analysis, the CD4-CD8- double-negative TB cell subtype was predominant, comprising over 90% in samples with abundant TLS infiltration and over 60% in samples with poor infiltration. This was followed by the CD4 + CD8- and CD4-CD8 + single-positive TB cell subtypes, while the CD4 + CD8 + double-positive TB cell subtype was nearly absent. During the maturation of TLS, the proportion of B cells gradually increased, while the proportion of CD4-CD8- T cell subtype decreased. TB cells extensively infiltrate the TLS regions in tumor tissues, with the double-negative subtype being predominant, potentially playing a crucial regulatory role in the local tumor immune microenvironment. This finding could facilitate the advancement of novel cancer treatment strategies.

Diotallevi F., Esposito M., Fargnoli M.C., Quaglino P., Mastorino L., Stingeni L., Hansel K., Feliciani C., Megna M., Gallo L., Legori A., Argenziano G., Balato A., Bardazzi F., Burlando M., et. al.

Palmoplantar psoriasis (PPp) has a profound negative impact on patients’ quality of life, and it represents a therapeutic challenge, as palms and soles are difficult to treat area. Although the efficacy profile of tildrakizumab has been well evaluated in the literature, data on its use for PPp are still limited. The objective of the study was to evaluate the efficacy and safety of tildrakizumab on moderate-to-severe plaque psoriasis with involvement of the palmoplantar area. A multicenter, retrospective, real-life study was performed enrolling patients with moderate-to-severe plaque psoriasis involving the palmoplantar area undergoing treatment with tildrakizumab with a follow-up of at least 52 weeks. At baseline, demographic and clinical data were assessed. Psoriasis severity was evaluated by using Psoriasis Activity Severity Index (PASI), body surface area (BSA), Psoriasis Global Assessment (PGA), Pruritus-Numerical Rating Scale (P-NRS) and Dermatology Life Quality Index (DLQI). Palmoplantar PASI (ppPASI) was used to evaluate psoriasis severity in the palmoplantar region. Clinical improvement was evaluated at each follow-up visit [week (W) 4, 16, 52]. A total of 99 patients were enrolled. A reduction in PASI, BSA, PGA, P-NRS and DLQI was observed at each time point. Mean ppPASI at baseline was 16.9 ± 13.2, which started to improve at W4 (8.9 ± 9.1) and continued to decrease at W16 (2.1 ± 3.1) and W52 (0.5 ± 1.0). Moreover, a sub-analysis showed that the probability of achieving ppPASI50 at W4 increased in case of nail psoriasis (p < 0.05) and decreased in bio-experienced patients (p < 0.001). Similarly, the probability of achieving ppPASI75 at W4 decreased in the case of prior biologic exposure (p < 0.05). Finally, patients with nail psoriasis showed a higher probability of reaching ppPASI75 at W16 (p < 0.05), whereas patients previously treated with systemic therapies for psoriasis reported a reduced probability of ppPASI75 achievement at this time point (p < 0.05). Tildrakizumab was shown to be a fast and effective treatment for patients with PPp, being able to achieve significant results already after only 4 weeks of treatment. Moreover, the identification of potential clinical factors predictive of response may improve the selection of the best treatment in patients with PPp.

Zhou X., Tang B., Huang Q., Yang S., Jiang Y., Xu L., Chen W., Shan G., Liao X., Hou C., Yao Z., Zou C., Ou R., Xu Y., Li D.

AbstractPsoriasis is a chronic inflammatory dermatosis driven by excessive activation of the immune system. Recent studies have demonstrated the therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) to psoriasis because of their immunomodulation functions. Yet, the outcome of MSC‐EVs alone is still unsatisfactory and the underlying mechanisms are also unclear. Here, it is uncovered that arginase1 (Arg1)/polyamine is overexpressed in psoriasis patients and murine, inducing the in‐situ accumulation of self‐antigens. Engineered nor@MSC‐EVs are fabricated by loading Arg1 inhibitor nor‐NOHA into MSC‐EVs for studying the therapeutic effect and mechanism of psoriasis. The nor@MSC‐EVs exhibited profound suppression of the NF‐κB signaling pathway by targeting Arg1/polyamine‐mediated DCs/Th17 axis through scavenging self‐antigens, resulting in superior mitigation of skin lesions and modulation of local and systemic metabolic and immunological disorders compared to the MSC‐EVs and clinically used anti‐IL17A both in vitro and in vivo. Together, the results highlight a novel perspective for psoriasis therapy by nor@MSC‐EVs with broad clinical translational potential.

Vangilbergen M., Stockman A., Van De Velde A., Garmyn M., Punie K., Hillary T.

Joshi S., Trivedi D.

Su C., Zhou Y., Xu G., Xue K., Wang G., Dang E.

Jairath V., Acosta Felquer M.L., Jaihyun Cho R.

Wride A.M., Chen G.F., Spaulding S.L., Tkachenko E., Cohen J.M.

Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.

Zhou Q., Shi R.

Background Increasing evidence suggests a higher propensity for acute myocardial infarction (MI) in patients with psoriasis. However, the shared mechanisms underlying this comorbidity in these patients remain unclear. This study aimed to explore the shared genetic features of psoriasis and MI and to identify potential biomarkers indicating their coexistence. Methods and Results Data sets obtained from the gene expression omnibus were examined using a weighted gene coexpression network analysis approach. Hub genes were identified using coexpression modules and validated in other data sets and through in vitro cellular experiments. Bioinformatics tools, including the Human microRNA Disease Database, StarBase, and miRNet databases, were used to construct a ceRNA network and predict potential regulatory mechanisms. By applying weighted gene coexpression network analysis, we identified 2 distinct modules that were significant for both MI and psoriasis. Inflammatory and immune pathways were highlighted by gene ontology enrichment analysis of the overlapping genes. Three pivotal genes—Src homology and collagen 1, disruptor of telomeric silencing 1‐like, and feline leukemia virus subgroup C cellular receptor family member 2—were identified as potential biomarkers. We constructed a ceRNA network that suggested the upstream regulatory roles of these genes in the coexistence of psoriasis and MI. Conclusions As potential therapeutic targets, Src homology and collagen 1, feline leukemia virus subgroup C cellular receptor family member 2, and disruptor of telomeric silencing 1‐like provide novel insights into the shared genetic features between psoriasis and MI. This study paves the way for future studies focusing on the prevention of MI in patients with psoriasis.

Sun X., Cui Z., Wang Q., Liu L., Ding X., Wang J., Cai X., Li B., Li X.

Formation of anti-drug antibodies (ADAs) against biologics is an important cause of psoriasis treatment failure. This study aimed to summarize the characteristics of ADAs formation under different biological therapies and the influence of ADAs on the clinical effects and safety of biologics in patients with psoriasis. PubMed, Embase, and Web of Science databases were searched from their inception to August 2022. Studies on biologics that assessed ADA levels in patients with psoriasis were included. The Cochrane risk-of-bias tool was used to assess the quality of randomized controlled trials (RCTs), the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control and cohort studies, and the Joanna Briggs Institute (JBI) critical appraisal checklist for single-arm studies. We calculated the pooled incidence with a random-effects model using R software. Subgroup analyses revealed that differences in patient characteristics, disease conditions, study design, and immunoassays may influence ADA generation and detection. The analysis included 86 studies, with a total population of 42,280 individuals. The pooled ADA rates were 0.49%, 2.20%, 2.38%, 4.08%, 7.38%, 7.94%, 14.29%, 21.93%, 29.70%, 31.76%, and 39.58% for secukinumab, etanercept, brodalumab, ustekinumab, tildrakizumab, guselkumab, ixekizumab, risankizumab, infliximab, adalimumab, and bimekizumab, respectively. >70% (95% CI, 0.71–0.81) of ADAs against adalimumab were neutralizing antibodies, and over 70% of ADAs against secukinumab and brodalumab were transient. Concomitant methotrexate therapy with tumor necrosis factor-α (TNF-α) inhibitors decreased ADA levels. Lower infliximab doses and intermittent therapy with interleukin (IL)-23 p19 inhibitors increased ADA formation. Additionally, ADA formation under treatment using TNF-α inhibitors and IL-12/23 p40 inhibitors was associated with lower response rates or serum drug levels, but only high ADA titers reduced the clinical effects of IL-17 inhibitors. The occurrence of IL-23 p19 and TNF-α inhibitors has been linked to injection-site reactions. Among the 11 biologics, secukinumab, etanercept, and brodalumab resulted in the lowest ADA formation rates. Immunogenicity contributes to lower biological efficacy and a higher likelihood of injection-site reactions. Low doses, intermittent treatment may increase ADA formation. An appropriate biologic should be selected based on the ADA formation rate and course of treatment.

Cardinez C., Hao Y., Kwong K., Davies A.R., Downes M.B., Roberts N.A., Price J.D., Hernandez R.A., Lovell J., Chand R., Feng Z., Enders A., Vinuesa C.G., Miraghazadeh B., Cook M.C.

AbstractLoss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.

Polesie S., Alinaghi F., Egeberg A.

Kridin K., Abdelghaffar M., Mruwat N., Ludwig R.J., Thaçi D.

AbstractBackgroundCancer risk after long‐term exposure to interleukin (IL)‐23 inhibitors (IL‐23i) and IL‐17 inhibitors (IL‐17i) remains to be delineated.ObjectiveTo evaluate the risk of malignancies in patients with psoriasis treated with IL‐23i and IL‐17i relative to those prescribed tumour necrosis factor inhibitors (TNFi) during the first 5 years following drug initiation.MethodsA global population‐based cohort study included two distinct analyses comparing patients with psoriasis under different therapeutic modalities; (i) new users of IL‐17i(n = 15,331) versus TNFi (n = 15,331) and (ii) new users of IL‐23i (n = 5832) versus TNFi (n = 5832).ResultsPatients prescribed IL‐17i experienced a decreased risk of non‐Hodgkin lymphoma (NHL; HR, 0.58; 95% CI, 0.40–0.82; p = 0.002), colorectal cancer (HR, 0.68; 95% CI, 0.49–0.95; p = 0.024), hepatobiliary cancer (HR, 0.68; 95% CI, 0.58–0.80; p < 0.001), ovary cancer (HR, 0.48; 95% CI, 0.29–0.81; p = 0.005), melanoma (HR, 0.52; 95% CI, 0.37–0.73; p < 0.001), and basal cell carcinoma (BCC; HR, 0.57; 95% CI, 0.48–0.67; p < 0.001). IL‐23i was associated with a reduced risk of NHL (HR, 0.39; 95% CI, 0.19–0.78; p = 0.006), hepatobiliary cancer (HR, 0.44; 95% CI, 0.31–0.62; p < 0.001) and BCC (HR, 0.76; 95% CI, 0.57–0.99; p = 0.046). In a sensitivity analysis comparing patients managed by IL‐17i and IL‐23i with their biologic‐naïve counterparts, these classes were associated with decreased risk of several malignancies.ConclusionIL‐17i and IL‐23i are associated with decreased risk of several malignancies. These findings should be considered prior to the prescription of biologics.

Bangert C., Loesche C., Skvara H., Fölster-Holst R., Lacour J., Jones J., Burnett P., Novak N., Stingl G.

Background The value, if any, of anti-IgE approaches in the treatment of atopic dermatitis has not been fully clarified. Studies using the anti-IgE omalizumab have yielded conflicting results. Objective Antibodies with an IgE-suppressive capacity stronger than omalizumab might be more efficacious. Study design We assessed the safety and efficacy of the high-affinity anti-IgE antibody ligelizumab (280 mg, subcutaneous, every other week) in 22 adult patients with moderate-to-severe atopic dermatitis in a placebo and active (cyclosporine A) controlled, randomized, multicenter, double-blind clinical trial for 12 weeks. Results We found that ligelizumab treatment resulted in either complete (patients with baseline IgE < 1,500 IU/ml) or partial (baseline IgE > 1,500 IU/ml) suppression of serum and cell-bound IgE as well as of allergic skin prick tests. On the other hand, ligelizumab—as opposed to cyclosporine A—was not significantly superior to placebo in inducing Eczema Area and Severity Index 50 response or significantly reducing pruritus and sleep disturbance. Interestingly though, patients with high baseline IgE exhibited a slightly but not significantly better treatment response than those with low baseline IgE. Conclusion Our study shows that an immunologically efficacious anti-IgE approach is not clearly superior to placebo in treating atopic dermatitis. Larger studies are needed to determine whether certain patient subgroups may benefit from this strategy. Trial registration: The study was registered in 2011 at clinicaltrialsregister.eu, EudraCT Number 2011-002112-84. The value, if any, of anti-IgE approaches in the treatment of atopic dermatitis has not been fully clarified. Studies using the anti-IgE omalizumab have yielded conflicting results. Antibodies with an IgE-suppressive capacity stronger than omalizumab might be more efficacious. We assessed the safety and efficacy of the high-affinity anti-IgE antibody ligelizumab (280 mg, subcutaneous, every other week) in 22 adult patients with moderate-to-severe atopic dermatitis in a placebo and active (cyclosporine A) controlled, randomized, multicenter, double-blind clinical trial for 12 weeks. We found that ligelizumab treatment resulted in either complete (patients with baseline IgE < 1,500 IU/ml) or partial (baseline IgE > 1,500 IU/ml) suppression of serum and cell-bound IgE as well as of allergic skin prick tests. On the other hand, ligelizumab—as opposed to cyclosporine A—was not significantly superior to placebo in inducing Eczema Area and Severity Index 50 response or significantly reducing pruritus and sleep disturbance. Interestingly though, patients with high baseline IgE exhibited a slightly but not significantly better treatment response than those with low baseline IgE. Our study shows that an immunologically efficacious anti-IgE approach is not clearly superior to placebo in treating atopic dermatitis. Larger studies are needed to determine whether certain patient subgroups may benefit from this strategy. Trial registration: The study was registered in 2011 at clinicaltrialsregister.eu, EudraCT Number 2011-002112-84.

Chua L., Friedrich S., Zhang X.C.

Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn’s disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis. Serum pharmacokinetic data in patients receiving mirikizumab 50–1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18–64%). The subcutaneous bioavailability of mirikizumab was 48%. Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required. ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).