Anti IL-12 Research Articles

Remission Factors for Ustekinumab Treatment of Ulcerative Colitis: A Multicenter Retrospective Study of Real-World Data in Japan

Ustekinumab (UST) is an anti–IL-12/23p40 monoclonal antibody used to treat inflammatory bowel disease. The aim of this retrospective, multicenter study was to investigate the effectiveness of UST administration in achieving remission in patients with ulcerative colitis (UC) and to determine patient characteristics that influence its effectiveness. Of 88 UC patients who received UST from March 2020 to August 2023, 47 with traceable data and for whom 56 weeks had elapsed since the start of treatment received UST to induce remission. The remission rates at 8 weeks were 66% overall, 73.7% for Bio Naïve (never used biologics/JAK inhibitors), and 60.7% for Bio Failure (used biologics/JAK inhibitors) groups. Remission rates at 56 weeks were 70.2% overall, 73.7% for Bio Naïve, and 67.9% for Bio Failure groups. Ustekinumab showed good mid-to-long-term results in the induction of remission of UC in both Bio Naïve and Bio Failure groups. The group showing remission at 8 weeks had a significantly higher non-relapse or continuation rate (proportion of patients with no worsened symptoms necessitating surgery/drug change) at 56 weeks. Predictive factors for achieving remission after UST in UC were female gender, low body mass index, and low lymphocyte-to-monocyte ratio. Thus, UST is effective for moderate-to-severe UC.

Formulary Management of Biologics in Plaque Psoriasis


 Unlike the new-generation biologics (interleukin [IL]-17 and IL-23 inhibitors), all old-generation biologics (anti–tumour necrosis factor [TNF] and anti–IL-12/23 biologics) for plaque psoriasis (PsO) have now lost their exclusivity status and most were launched prior to the pan-Canadian Pharmaceutical Alliance. In addition, biosimilar versions of the old-generation biologics have had limited uptake and delayed launches in Canada spanning multiple years, suggesting a significant opportunity cost paid for these drugs after loss of exclusivity.
 Modern clinical evidence, which is more rigorous than the evidence supporting the old-generation drugs and includes head-to-head trials comparing IL-17 and IL-23 inhibitors with anti-TNF and anti–IL-12/23 biologics, have demonstrated greater efficacy with the new-generation biologics.
 In Canada, despite access to newer and more efficacious treatments, physicians continue to prescribe old-generation drugs to patients newly initiating a biologic for PsO (25% of patients in 2020), and the new-generation biologics are also less costly on an average per patient basis at list price compared with the most utilized old-generation biologic (ustekinumab).
 Public payers have spent $28 million (at list price) on biologics initiated for PsO beyond their loss of exclusivity from 2016 to 2020 ($600 million for biologics initiated for any indication), and that figure is likely much higher today. Notably, some IL-17 biologics will lose data protection within the next 2 years, which will further increase this opportunity cost.
 It is prudent that decision-makers review the place in therapy of biologics for PsO. Based on the findings of this report, the policy recommendation is to assess the clinical and economic value of old-generation biologics in the context of current evidence standards in PsO. The promotion of the use of new-generation biologics should be considered by payers to support the appropriate use of biologics in PsO, which would improve patient outcomes with budget savings or neutrality (assuming no confidential pricing agreements with the old-generation biologics) versus the status quo.

Immunomodulatory Agents for Treatment of Patients with Inflammatory Bowel Disease (Review safety of anti-TNF, Anti-Integrin, Anti IL-12/23, JAK Inhibition, Sphingosine 1-Phosphate Receptor Modulator, Azathioprine / 6-MP and Methotrexate).

As treatment options for Inflammatory Bowel Disease (IBD) expand each class of medication will have specific safety concerns and side-effect profiles that need to be considered for optimal treatment of patients. We will review the most recent safety data for the newly approved immunomodulator therapies for the treatment of IBD. There are a growing number of publications outlining safety concerns for medications used to treat IBD. We reviewed safety profile of anti-tumor necrosis factor antibodies (TNF) with specific attention to combination therapy (anti-TNF plus immunomodulator). Recent publications have demonstrated increased risk of serious infection and malignancy (lymphoma and overall cancer rates) in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immunomodulator monotherapy. Recent publications on Janus Kinase Inhibitors indicate an increased risk of infection, specifically Herpes Zoster, and increased risk of major cardiovascular events and venous thromboembolic events resulting in a black box warning for the medication. In contrast, anti-interleukin 12/23 agents and gut selective anti-integrin antibody agents have demonstrated a favorable side-effect profile with low rates of infection and malignancy. The latest class of medications to be approved, sphingosine 1-phosphate (S1P) receptor modulators, have cardiac and infectious precautions. The field of IBD treatment is rapidly evolving with several mechanistic classes of medications now available. While corticosteroids continue to be associated with the greatest, overall, safety risks, each of the newer mechanistic classes have unique safety concerns. In the future, as we gain more experience with these agents, we will need to continue to evaluate the safety profile of our therapies used alone or in combination to make informed treatment decisions with our patients.

Guselkumab and risankizumab for psoriasis: a 44-week indirect real-life comparison

Guselkumab and risankizumab for psoriasis: a 44-week indirect real-life comparison

A systematic review of eczematous eruptions in patients receiving biologic therapy

A systematic review of eczematous eruptions in patients receiving biologic therapy

P415 The anti-IL-23/IL-12 agent Ustekinumab is an effective and safe induction therapy in patients with Crohn’s disease refractory or intolerant to anti-TNF: a multicentre Italian study

Abstract Background There are limited real-life studies in medical literature evaluating the efficacy and safety of Ustekinumab, an Anti-IL-23/Anti IL-12 agent, in patients with Crohn’s disease (CD) who required treatment because of refractoriness or intolerance to previous biological treatments. Thus, the aim of this study was to assess the effectiveness and tolerability of Ustekinumab in anti-TNF refractory or intolerant CD patients. Methods All CD patients who completed induction with Ustekinumab in three Italian IBD Units (Padua, Santorso, and Pisa) were enrolled. Patients were evaluated after induction (first intravenous dose followed by a subcutaneous dose at 8 weeks) and clinical (Harvey- Bradshaw-Index) and biochemical data, including faecal calprotectin (FC) and C-reactive protein (CRP) were collected. Information on the need of optimisation (every 12 or 8 weeks) and adverse events were also collected. Continuous and categorical variables were expressed as mean with standard deviation (sd) and frequency with percentages, respectively. Comparisons between variables were conducted using paired t-test and chi-square test. Data were analysed using STATA11.1 software. Results Sixty-three patients were included (41 males, mean age 43 ± sd 13.2 years). All of them had previously been treated with at least one biologic agent and 95.2% with oral steroids. The main indications for starting therapy were: previous treatment failure (77.2%) and pharmacological intolerance (17.5%). At the time of the induction, 28.6% patients were under steroid treatment. Post induction, clinical remission was obtained in 63.5% patients, while steroid-free clinical remission in 52.4%. Moreover, a statistically significant reduction of FC (from 916 μg/l to 444 μ/l, p < 0.001) and normalisation of CRP (n = 14, 33.3%; p < 0.001) were observed. After induction, 3 adverse effects were reported, and in two treatment discontinuations was necessary (i.e. 1 case of pyelonephritis and 1 case of a re-activation of entero-cutaneous fistula). Finally, among 63 patients enrolled, 51 (80.9%) were optimised with a maintenance regimen of 8 weeks sub-cutaneous doses. Conclusion Our study shows that Ustekinumab seemed is effective in achieving clinical remission and steroid-free clinical remission after induction in the majority of CD patient despite the refractoriness to anti-TNF treatment. Moreover, the drug appeared safe and well tolerated. On the other hand, treatment optimisation to 8 weeks was adopted in most of the patients, in order to guarantee a better outcome.

New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody.

92 Background: Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Methods: We constructed 3 recombinant oHSVs expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). We compared 1) the oncolytic effects of a single or multiple intratumoral injection(s) of T1, T2 and T3 series oHSVs, 2) the effectiveness of intratumoral injection of T3 oHSV with systemic administration of anti PD-1 ab and IL12 alone or in combinations with T1. Results: Insertion of gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). In syngeneic mice the T3 series oHSV expressing murine IL-12 and PD-1 Ab was effective against a variety of murine tumors. Concurrent with enhanced cytolytic activity the T3 induced significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ. Consistent with an earlier report of an inverse correlation between the volume of the tumor and the quantity of retained IFN-γ. The most effective oncolytic effect resulted from the administration of T3855 expressing both IL12 and anti PD-1 antibody or T2850 concurrently with intraperitoneal administration of anti PD-1 antibody alone. The least effective were single intraperitoneal administration of IL12 or PD-1 antibody. Intratumoral injection of T3 oHSV was most effective against murine tumors in comparison of either systemic administration of anti PD-1 ab and IL12 or intratumoral injection of T1 in combinations of systemic administration of anti PD-1 ab and IL12. Conclusions: We report the marriage in a single therapeutic agent of three distinct cancer therapies: the targeting of cancer cells by oncolytic viruses, the stimulation of immune system by IL12, and the production of immunotherapeutic antibodies against PD-1. The significant finding reported in this article is that the anti-tumor responses remain concentrated in the tumor environment.

Crohn\u2019s-like disease in a patient exposed to anti-Interleukin-17 blockade (Ixekizumab) for the treatment of chronic plaque psoriasis: a case report

BackgroundPlaque psoriasis and inflammatory bowel disease (IBD) are both chronic immune-mediated inflammatory diseases with an overlapping genetic profile and have been linked in epidemiological studies. Psoriasis and IBD share similar components in their inflammatory pathways and animal and human studies have suggested a potential role for targeting interleukin (IL)-17 with novel antibody therapies in the treatment of these diseases. These studies, while promising for psoriasis, have been associated with deterioration in patients with IBD. Post-hoc analyses of clinical trials involving Ixekizumab revealed adverse outcomes in a small cluster of patients with IBD, prompting recommendations to monitor this population with the use of this drug.Case presentationForty-two year old Caucasian male with treatment-refractory chronic plaque psoriasis who developed new onset diarrheal illness and rectal bleeding following a 12 week induction period with Ixekizumab (anti-IL-17 neutralizing antibody). Colonoscopy revealed severe ulceration throughout the ascending and transcending colon. Histopathology, combined with endoscopic findings, led to a diagnosis of Crohn’s-like colitis. The patient’s anti-IL-17 medication was discontinued and endoscopic remission was induced with the use of corticosteroids, escalated anti-TNF therapy and eventually anti IL-12/23 neutralizing antibody (ustekinumab).ConclusionMurine studies implicate IL-17 and the downstream effects of its inhibition, in the breakdown of the gut epithelial layer, the disruption of normal host immune responses and the propagation of intestinal inflammation. The increasing use of IL-17 inhibitors has led to reports of exacerbation and potential development of inflammatory bowel disease. While clinical trials have revealed clusters of new inflammatory bowel disease cases amongst psoriasis patients using an IL-17 inhibitor, there remains a lack of evidence to suggest a causal relationship. This is the first case report of de-novo severe Crohn’s-like IBD in association with the use of Ixekizumab requiring rescue with escalated dosing of anti-TNF therapy and highlights the importance of close monitoring in patients being treated with IL-17 inhibitors, especially in those patients with known risk factors for inflammatory bowel disease.

Abstract LB-078: New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody

Abstract Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Here we report the properties of 3 families of oHSV expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). Thus insertion of the genes encoding PD-1 Ab and IL-12 significantly augmented the oncolytic activity of oHSV bereft of immune-stimulatory genes (T1 series). In syngeneic mice the murine T3 oHSV induced significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ and was effective against a variety of murine tumors. Thus T3 oHSV concentrates the immunomodulatory products in the environment of the tumors thereby reducing the risk of toxicity associated with systemic administration. T3 oHSV injected into tumors was more effective than systemic administration of anti PD-1 Ab and IL12 alone or in combination with intratumoral injection of T1 oHSV. T3 induces local and systemic immune response characterized by cytokine signature. Citation Format: Grace Zhou, Dongyao Ni, Runbin Yan, Xiaoqing Chen, Xianjie Liu, Jie Ma, Yuxin Tang. New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-078.

New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody.

e14250 Background: Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Methods: We constructed 3 families of recombinant oHSVs expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). We compared the oncolytic effects of a single or multiple intratumoral injection(s) of T1, T2 and T3 series oHSVs. We also compared the effectiveness of intratumoral injection of T3 oHSV with systemic administration of anti PD-1 ab and IL12 alone or in combinations with T1. Results: Insertion of the gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). In syngeneic mice the T3 series oHSV expressing murine IL-12 and PD-1 Ab was effective against a variety of murine tumors. Concurrent with enhanced cytolytic activity the T3 oHSV induced the production and significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ. Consistent with an earlier report we noted an inverse correlation between the volume of the tumor and the quantity of retained IFN-γ. The most effective oncolytic effect resulted from the administration of T3855 expressing both IL12 and anti PD-1 antibody or T2850 concurrently with intraperitoneal administration of anti PD-1 antibody alone. The least effective were single intraperitoneal administration of IL12 or PD-1 antibody. Intratumoral injection of T3 oHSV was most effective against murine tumors in comparison of either systemic administration of anti PD-1 ab and IL12 or intratumoral injection of T1 in combinations of systemic administration of anti PD-1 ab and IL12. Conclusions: We report the marriage in a single therapeutic agent of three distinct cancer therapies: the targeting of cancer cells by oncolytic viruses, the stimulation of immune system by IL12, and the production of immunotherapeutic antibodies against PD-1. The significant finding reported in this article is that the anti-tumor responses remain concentrated in the tumor environment.

Treatment of Dactylitis and Enthesitis in Psoriatic Arthritis with Biologic Agents: A Systematic Review and Metaanalysis.

Biologic agents with different mechanisms of action [inhibitors of tumor necrosis factor-α (TNF-α), interleukin (IL)-12/23, and IL-17] showed efficacy in randomized controlled trials (RCT) in the treatment of psoriatic arthritis. We conducted a pooled metaanalysis of these agents for treatment of dactylitis and enthesitis and compared results with the American College of Rheumatology 20 (ACR20) response and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. A systematic literature search was performed and a pooled metaanalysis of RCT with anti-TNF-α (infliximab, golimumab, adalimumab), anti-IL-12/23 (ustekinumab), and anti-IL-17 (secu kinumab, ixekizumab) was conducted using the random-effects model. Bias was assessed using the Cochrane risk-of-bias tool. Eighteen RCT were included in the pooled analysis (n = 6981). Both TNF-α inhibitors and novel biologics (ustekinumab, secukinumab, ixekizumab) demonstrated significant resolution of dactylitis at Week 24 with pooled risk ratios (RR) versus placebo of 2.57 (95% CI 1.36-4.84) and 1.88 (95% CI 1.33-2.65), respectively. For resolution of enthesitis at Week 24, RR for TNF-α inhibitors was 1.93 (95% CI 1.33-2.79) versus 1.95 (95% CI 1.60-2.38) for novel biologics. Both biologic categories showed overlapping ranges of ACR20 responses (TNF-α inhibitors: RR = 2.23, 95% CI 1.60-3.11; pooled IL-12/23 and -17: RR = 2.30, 95% CI 1.94-2.72) and similar quality of life improvement scores with mean HAQ-DI score changes of -0.29 (95% CI -0.39 to -0.19) and -0.26 (95% CI -0.31 to -0.22), respectively. The pooled analysis demonstrated that anti-TNF-α agents have the same efficacy as novel agents (ustekinumab, secukinumab, and ixekizumab) in dactylitis and enthesitis.

Lysyl-Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-κB Pathways, Strongly Contributing to Enhanced Th1 Cell Responses.

In addition to essential roles in protein synthesis, lysyl-tRNA synthetase (KRS) is secreted to trigger a proinflammatory function that induces macrophage activation and TNF-α secretion. KRS has been associated with autoimmune diseases such as polymyositis and dermatomyositis. In this study, we investigated the immunomodulatory effects of KRS on bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and subsequent polarization of Th cells and analyzed the underlying mechanisms. KRS-treated DCs increased the expression of cell surface molecules and proinflammatory cytokines associated with DC maturation and activation. Especially, KRS treatment significantly increased production of IL-12, a Th1-polarizing cytokine, in DCs. KRS triggered the nuclear translocation of the NF-κB p65 subunit along with the degradation of IκB proteins and the phosphorylation of MAPKs in DCs. Additionally, JNK, p38, and ERK inhibitors markedly recovered the degradation of IκB proteins, suggesting the involvement of MAPKs as the upstream regulators of NF-κB in the KRS-induced DC maturation and activation. Importantly, KRS-treated DCs strongly increased the differentiation of Th1 cells when cocultured with CD4+ T cells. The addition of anti-IL-12-neutralizing Ab abolished the secretion of IFN-γ in the coculture, indicating that KRS induces Th1 cell response via DC-derived IL-12. Moreover, KRS enhanced the OVA-specific Th1 cell polarization in vivo following the adoptive transfer of OVA-pulsed DCs. Taken together, these results indicated that KRS effectively induced the maturation and activation of DCs through MAPKs/NF-κB-signaling pathways and favored DC-mediated Th1 cell response.

Effect of anti IL-12/23 on body composition: results of bioelectrical impedance analysis in Caucasian psoriatic patients

ABSTRACTBackground: Bioelectrical impedance analysis (BIA) is an inexpensive, non-invasive and fast method to assess body composition. Little is known of the interaction between anti IL 12/23 treatment and body composition. The aim of this study was to evaluate 6- and 12-month changes in body weight, Body Mass Index (BMI) and body composition assessed by BIA in psoriatic patients treated with anti-IL-12/23.Research design and methods: Demographic and clinical data were collected for each enrolled patient. Physical examination, anthropometric assessment, Psoriasis Area and Severity Index (PASI) assessment and body composition by BIA (single-frequency 50 kHz), were assessed at baseline and at 6 and 12 months of treatment.Results: A significant decrease in body weight, compared to baseline, in BMI, Fat Mass at month 6 and a significant increase at month 12 for body cellular mass (BCM) and Phase Angle (PhA) were observed. In addition, a significant increase was found for intracellular water.Conclusion: At baseline, psoriatic patients showed a lower BCM and a lower mean PhA score. During ustekinumab treatment, the mean PhA and BCM scores increased with an improvement in psoriatic disease. Thus, ustekinumab can be an effective drug for improving not only psoriasis but also the general clinical status of patients.

IL-1β enhances inflammatory TH2 differentiation

IL-1β enhances inflammatory TH2 differentiation

Biological therapy induces expression changes in Notch pathway in psoriasis.

Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

Quando anti‐TNF não obtém sucesso, anti‐IL‐12‐23 é opção alternativa na psoríase e na artrite psoriásica

Patients with psoriasis and psoriatic arthritis respond to anti–TNF therapy, but not all patients maintain effective response, and some do not respond. In this article, we demonstrate the role of a new pathogenetic pathway to some extent TNF–independent in these patients. Anti–IL12–23 is a new and alternate mode of therapy for patients with recalcitrant response to anti–TNF.

Increased expression of IL‐17A and limited involvement of IL‐23 in patients with palmo‐plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial

Palmo-plantar pustular psoriasis (PPPP) and palmo-plantar pustulosis (PPP) are chronic skin diseases with significant impact on quality of life. The purpose of this study was to study the efficacy of ustekinumab in PPPP and PPP and gain more knowledge on the pathophysiology and the role of the interleukin-23 (IL-23) signalling pathway in these diseases. Thirty-three patients with either PPPP (20) or PPP (13) and seven volunteers with normal palmo-plantar skin were recruited. Patients with PPP or PPPP were randomised (1:1) to receive either an anti IL-12/IL-23 antibody (ustekinumab 45mg) or placebo at day 0 and week 4 with subsequent placebo cross-over to ustekinumab at week 16. The primary endpoint was the proportion of patients randomized to ustekinumab achieving a 50% improvement in the Palmo-Plantar Pustular Area and Severity Index (PPPASI-50) as compared to placebo. Skin biopsies of the palms and soles of normal subjects and patients with PPP or PPPP were performed and analysed by RT-PCR and immunohistochemistry. There was no statistically significant difference in the proportion of patients randomised to ustekinumab as compared to those randomised to placebo achieving PPPASI-50 at week 16 for patients with PPPP (10%, 20%; P=1.000) or PPP (20%, 37.5%; P=1.000) respectively. Compared to normal subjects an 89-fold increase in IL-17A expression was found in palms/soles of patients with PPPP (P=0.006) and a 190-fold increase for patients with PPP (P=0.051). There were no statistically significant changes in cytokine expression at week 16 in the palms and soles of patients with PPP or PPPP. Taken together these results suggest that ustekinumab at a dose of 45mg has limited efficacy in PPPP and PPP. IL-17A may have a more important role than IL-23 in patients with PPPP and PPP. Conclusions are limited by the small sample size of this study.

Th17 Cells Carrying TCR Recognizing Epidermal Autoantigen Induce Psoriasis-like Skin Inflammation

Psoriasis is considered a Th17-type autoimmune skin inflammatory disease; however, involvement of an autoantigen-specific TCR has not been established. In this study, we show that psoriasis-like skin inflammation can be induced by autoreactive Th17 cells. We previously developed the desmoglein 3-specific TCR-transgenic (Dsg3H1) mouse, in which CD4⁺ T cells recognize physiological epidermal autoantigen. T cells from Dsg3H1 mice were polarized into Th17 cells in vitro and then adoptively transferred into Rag2⁻/⁻ mice. Dsg3H1-Th17 cells induced severe psoriasis-like skin inflammation within 2 wk after transfer in the tissues in which desmoglein 3 is expressed. Such pathology was not observed when wild-type Th17 cells or Th1-skewed Dsg3H1 T cells were transferred, and it was strongly suppressed by anti-IL-12/23 and anti-IL-17 Abs. Although IFN-γ⁺/IL-17⁺ T cells accumulated in the skin lesions of mice that received Dsg3H1-Th17 cells, IFN-γ-deficient Dsg3H1-Th17 cells were fully pathogenic. These results demonstrate that cutaneous psoriasis-like immunopathology can be developed by epidermis-specific recognition of Th17 cells, which is strictly dependent on IL-17 but not IFN-γ.

The Use of Anti–Interleukin-12/23 Agents and Major Adverse Cardiovascular Events

Question: Is the use of anti–interleukin (IL)-12 and IL-23 agents to treat chronic plaque psoriasis associated with an increase in major adverse cardiovascular events? Objective: To evaluate a possible association between biologic therapies for CPP [chronic plaque psoriasis] and MACEs [major adverse cardiovascular events] via metaanalysis. Data Sources: Randomized controlled trials (RCTs) of anti–IL-12/23 (ustekinumab and briakinumab) agents and anti–tumor necrosis factor (TNF) agents (adalimumab, etanercept, and infliximab) used in treating CPP were reviewed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ovid MEDLINE from database inception to May 2011. The results of registered nonpublished completed studies were procured through abstract publications or poster presentations. Study Selection: Randomized, placebo-controlled, doubleblind, monotherapy studies (with safety outcome data for MACE) of IL-12/23 antibodies and anti–TNFagents in adults. Studies of psoriatic arthritis were excluded. Data Extraction: Two investigators independently searched data while 6 investigators reviewed the abstracted data. Results: A total of 22 RCTs comprising 10 183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least 1 dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I statistic (I=0), allowing for combination of trial results using the MantelHaenszel fixed-effects method. During the placebocontrolled phases of the anti–IL-12/23 studies, 10 of 3179 patients receiving anti–IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person-year; 95% confidence interval [CI], −0.001 to 0.026; P=.12). In the anti–TNFtrials, only 1 of 3858 patients receiving anti–TNFagents experienced a MACE compared with 1 of 1812 patients receiving placebo (Mantel-Haenszel risk difference, −0.0005 events/personyear; 95% CI, −0.010 to 0.009; P=.94). Authors’ Conclusions: Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti– TNFtreatments. This study may have been underpowered to identify a significant difference.

Adiponectin Induces Dendritic Cell Activation via PLCγ/JNK/NF-κB Pathways, Leading to Th1 and Th17 Polarization

Adiponectin (APN) is a crucial regulator for many inflammatory processes, but its effect on Th cell-mediated responses has not been fully understood. Thus, we investigated the immune-modulatory effects of APN on dendritic cells (DCs) controlling Th cell polarization. APN induced maturation and activation of DCs, as demonstrated by the increased expression of MHC class II, costimulatory molecules in both mouse and human DCs, and it significantly enhanced production of proinflammatory cytokines. APN triggered degradation of IκB proteins, nuclear translocation of NF-κB p65 subunit, and phosphorylation of MAPKs in DCs. Pretreatment with a phospholipase C (PLC)γ inhibitor and a JNK inhibitor suppressed IL-12 production and NF-κB binding activity. Additionally, PLCγ inhibitor downregulated phosphorylation of JNK, indicating that PLCγ and JNK may be upstream molecules of NF-κB. Importantly, APN-treated DCs significantly induced both Th1 and Th17 responses in allogeneic CD4(+) T cells. The addition of a neutralizing anti-IL-12 mAb to the cocultures abolished the secretion of IFN-γ, whereas the blockage of IL-23 and IL-1β suppressed APN-induced IL-17 production. Immunization of mice with OVA-pulsed, APN-treated DCs efficiently led to Ag-specific Th1 and Th17 cell responses. Taken together, these results demonstrated that APN effectively induced activation of DCs through PLCγ/JNK/NF-κB-signaling pathways, leading to enhanced Th1 and Th17 responses.