Drug survival superiority of tumor necrosis factor inhibitors and interleukin-17 inhibitors over Janus kinase inhibitors and interleukin-12/23 inhibitors in German psoriatic arthritis outpatients: retrospective analysis of the RHADAR database.

Objective: Treatment options with disease-modifying antirheumatic drugs (DMARDs) for psoriatic arthritis (PsA) have evolved over recent years. In addition to Janus kinase inhibitors (JAKi), four classes of biologic DMARDs (bDMARDs; interleukin [IL]-23 inhibitors [IL-23i], IL-12/23 inhibitors [IL-12/23i], tumor necrosis factor inhibitors [TNFi], and IL-17 inhibitors [IL-17i]) are currently approved for moderate to severe PsA treatment. There is minimal evidence of the persistence of these drugs among PsA outpatients in a real-world scenario during the period following the approval of JAKi. Therefore, we aimed to analyze the drug survival rates of biologic and JAKi therapies among German PsA outpatients during routine clinical care. Methods: We retrospectively analyzed PsA patients with a new prescription for a biologic or JAKi in the RHADAR database between January 2015 and October 2023. Kaplan-Meier Curves and Cox regression modelling were used to compare drug survival rates. Results: 1352 new prescriptions with bDMARDs (IL-12/23i [n=50], IL-23i [n=31], TNFi [n=774], IL-17i [n=360]) or JAKi (n=137) were identified. The 5-year drug survival rate was 67.8% for IL-17i, 62.3% for TNFi, 53.3% for JAKi, and 46.0% for IL-12/23i. Discontinuation probabilities for JAKi and IL-12/23i were significantly higher compared with TNFi (JAKi hazard ratio [HR] 1.66, [95% CI 1.23-2.24], p=0.001; IL-12/23i HR 1.54, [95% CI 1.02-2.33], p=0.042) and IL-17i (JAKi HR 1.77, [95% CI 1.27-2.47], p=0.001; IL-12/23i HR 1.64, [95% CI 1.06-2.55], p=0.027). JAKi-treated patients had more severe disease and more osteoarthritis (OA) compared to TNFi and more OA compared to IL-17i. Conclusion: German PsA outpatients might persist longer with TNFi and IL-17i compared with IL-12/23i or JAKi. For TNFi, differences in subgroup characteristics and comorbidities (OA) may have affected drug survival rates. For IL-17i, the longer drug survival might not only be related to less OA compared to JAKi and, therefore, might be affected by other factors.

Biologics for Psoriasis.

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.

Anti-Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency.

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Psoríase vulgar grave com resposta satisfatória ao uso de anti-interleucina 12/23 (ustequinumabe): relato de caso / Severe psoriasis vulgar with satisfactory response to the use of anti-interleukin 12/23 (ustekinumab): case report

Introdução: A psoríase é uma doença inflamatória crônica imunomediada que acomete a pele e outros órgãos e que está fortemente associada a diversas comorbidades, incluindo doenças cardiovasculares, acidentes vasculares encefálicos, doença renal crônica e distúrbios psiquiátricos. Portanto, é fundamental entender a psoríase não como uma patologia estritamente dermatológica, mas sim multissistêmica. Objetivo: Relatar o caso de uma paciente com psoríase vulgar grave, a fim de auxiliar outros profissionais de saúde no diagnóstico precoce e tratamento eficaz desta doença. Resultado: Paciente feminina, 22 anos, procurou consultório privado referindo apresentar "lesões no corpo todo". Apresentava placas eritematoescamosas em dorso, tronco, membros superiores, membros inferiores. Após inúmeros tratamentos inefetivos, optado por iniciar o tratamento com uma droga anti-interleucina 12 e 23 como Ustequinumabe. Após 30 dias da dose de indução, antes da aplicação da segunda dose de indução, a paciente já apresentava melhora clínica satisfatória. Conclusão: O diagnóstico precoce é fundamental para a administração da terapêutica adequada, que, apesar de não promover a remissão da doença, corrobora para o controle da inflamação sistêmica, cujas implicações aumentam o risco de morbimortalidade dos pacientes

Introduction: Psoriasis is a chronic immune-mediated inflammatory disease that affects the skinand other organs and is strongly associated with several comorbidities, including cardiovascular disease, stroke, chronic kidney disease and psychiatric disorders. Therefore, it is fundamental to understand psoriasis not as a strictly dermatological pathology, but as a multisystemic one. Objective: To report the case of a patient with severe psoriasis vulgaris, in order to help other health professionals in the early diagnosis and effective treatment of this disease. Result: Patient female, 22 years old, looked for a private practice referring to having "injuries all over her body". She had erythematous, scaly plaques on her back, trunk, upper limbs, and lower limbs. After numerousineffective treatments, she opted to start treatment with an anti-interleukin 12 and 23 drug like Ustekinumab. Thirty days after the induction dose, before the application of the second induction dose, the patient already showed satisfactory clinical improvement. Conclusion: Early diagnosis is fundamental for the administration of adequate therapy, which, despite not promoting disease remission, contributes to the control of systemic inflammation, whose implications increase the risk of morbidity and mortality of patients

Introducción: La psoriasis es una enfermedad inflamatoria crónica inmunomediada que afecta la piel y otros órganos y está fuertemente asociada con varias comorbilidades, que incluyen enfermedad cardiovascular, accidente cerebrovascular, enfermedad renal crónica y trastornos psiquiátricos. Por tanto, es fundamental entender la psoriasis no como una patología estrictamente dermatológica, sino como multisistémica. Objetivo: Reportar el caso de un paciente con psoriasis vulgar severa, con el fin de ayudar a otros profesionales de la salud en el diagnóstico precoz y tratamiento efectivo de esta enfermedad. Resultado: Paciente mujer, 22 años, buscó una oficina privada, refiriéndo se a tener "lesiones en todo el cuerpo". Presentaba placas eritematosas, descamativas en espalda, tronco, miembros superiores e inferiores. Después de numerosos tratamientos ineficaces, optó por iniciar un tratamiento con un fármaco antiinterleucina 12 y 23 como Ustekinumab. Treinta días después de la dosis de inducción, antes de la aplicación de la segunda dosis de inducción, el paciente ya mostraba una mejoría clínica satisfactoria. Conclusión: El diagnóstico precoz es fundamental para la administración de una terapia adecuada que, a pesar de no promover la remisión de la enfermedad, apoye el control de la inflamación sistémica, cuyas implicaciones aumentan el riesgo de morbimortalidad de los pacientes

Treatment Options and Goals for Patients with Generalized Pustular Psoriasis.

Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or without systemic inflammation. GPP flares can be life-threatening if untreated due to potential severe complications such as cardiovascular failure and serious infections. Currently, there are no GPP-specific therapies approved in the USA or Europe. Retinoids, cyclosporine, and methotrexate are the most commonly used non-biologic therapies for GPP. The evidence that supports the currently available treatment options is mainly based on case reports and small, open-label, single-arm studies. However, recent advances in our understanding of the pathogenic mechanisms of GPP and the identification of gene mutations linked to the disease have paved the way for the development of specific targeted therapies that selectively suppress the autoinflammatory and autoimmune mechanisms induced during GPP flares. Several biologic agents that target key cytokines involved in the activation of inflammatory pathways, such as tumor necrosis factor-α blockers and interleukin (IL)-17, IL-23, and IL-12 inhibitors, have emerged as potential treatments for GPP, with several being approved in Japan. The evidence supporting the efficacy of these agents is mainly derived from small, uncontrolled trials. A notable recent advance is the discovery of IL36RN mutations and the central role of IL-36 receptor ligands in the pathogenesis of GPP, which has defined key therapeutic targets for the disease. Biologic agents that target the IL-36 pathway have demonstrated promising efficacy in patients with GPP, marking the beginning of a new era of targeted therapy for GPP.

Effects of TNF inhibitors and an IL12/23 inhibitor on changes in body weight and adipokine levels in psoriasis patients: a 48-week comparative study.

BACKGROUND: Psoriasis is a chronic inflammatory disease associated with obesity and metabolic syndrome. Adipokines are thought to be a link between psoriasis and obesity. Leptin, adiponectin, and omentin are bioactive adipokines thought to play a role in both metabolic comorbidities and inflammation. Anti-tumour necrosis factor alfa (anti-TNF-α) agents are effective for psoriasis treatment, although significant weight gain has been reported during anti-TNF-α therapy. The interleukin 12/23 (IL 12/23) inhibitor ustekinumab is also effective for psoriasis treatment. We compared the effects of three anti-TNF-α drugs and an IL-12/23 inhibitor on adipokines and weight gain during treatment. PATIENTS AND METHODS: This prospective study included 80 patients (37 women, 43 men) with moderate to severe plaque psoriasis whose age and weight were matched. The patients were divided into four equal groups: etanercept, infliximab, adalimumab, and ustekinumab treatment groups. Psoriasis Area Severity Index (PASI) score, body weight (muscle and fat compartments), and leptin, adiponectin, and omentin levels were evaluated at baseline and weeks 4, 12, 24, and 48 of treatment. RESULTS: There were no differences between drug groups in terms of weight parameters or biochemical parameters at baseline. At the end of 48 weeks, there was significant weight gain in the adalimumab group. Patients who received infliximab showed significant weight gain by week 12, but in the following weeks they returned to their initial weight. Body weight reached a maximum level by week 12 in patients using etanercept, but they lost weight in the following weeks and finished the study below their initial weight. Patients using ustekinumab did not demonstrate significant weight change during the 48 weeks except at week 12. At the end of week 48, PASI75 (improvement in PASI ≥75%) response rates were approximately 85% for the ustekinumab group, 80% for the adalimumab group, 75% for the infliximab group, and 50% for the etanercept group. Leptin, adiponectin, and omentin levels were higher in the ustekinumab group at all weeks except baseline. The lowest levels were observed in the etanercept group. The treatment response rate was also lower in the etanercept group. LIMITATIONS: We did not evaluate visfatin and resistin levels, insulin sensitivity, and cardiovascular risk that may be associated with weight gain and adipokine levels. CONCLUSIONS: Unlike TNF inhibitors, ustekinumab does not cause significant weight changes and it increases adipokine levels more than TNF inhibitors. Adipokine levels seem to be related to the treatment response.

Real-world biologic and apremilast treatment patterns in patients with psoriasis and psoriatic arthritis.

PURPOSE: Real-world treatment patterns among psoriasis patients with and without psoriatic arthritis (PsA) newly initiating treatment with a biologic or apremilast were assessed. PATIENTS AND METHODS: MarketScan claims data from adults with psoriasis and ?1 new prescription for secukinumab, adalimumab, ustekinumab, etanercept, or apremilast from January 1, 2015, to August 31, 2018, were assessed for adherence, switching, and combination therapy by index medication and PsA diagnosis. RESULTS: At treatment initiation, 22.0%-45.7% of patients had PsA. Over 24 months, discontinuation rates were high (34.4%-54.6%) overall and higher in patients with versus without PsA (all P<0.05 except secukinumab). Adherence was poor (16.8%-34.8%); switching and combination therapy were common. CONCLUSION: Treatment patterns varied, with better outcomes in PsA patients receiving anti-tumor necrosis factor versus anti-IL17/IL12/23 agents.

Effectiveness of IL-12/23 inhibition (ustekinumab) versus tumour necrosis factor inhibition in psoriatic arthritis: observational PsABio study results.

OBJECTIVES: To evaluate 6-month effectiveness of ustekinumab versus tumour necrosis factor inhibitor (TNFi), analysing predictors of low disease activity (LDA)/remission. METHODS: PsABio is a prospective, observational cohort study of patients with psoriatic arthritis (PsA) at 92 sites in eight European countries, who received first-line to third-line ustekinumab or a TNFi. Comparative achievement at 6 months of clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) LDA/remission, and minimal disease activity (MDA)/very LDA using propensity score (PS)-adjusted multivariate logistic regression was assessed. RESULTS: In the final analysis set of 868 participants with 6-month follow-up data (ustekinumab, n=426; TNFi, n=442), with long-standing disease and a high mean cDAPSA score (31.0 vs 29.8, respectively), proportions of patients in ustekinumab/TNFi treatment groups achieving cDAPSA LDA at 6 months were 45.7%/50.7%. cDAPSA remission was achieved in 14.9%/19.2%, and MDA in 26.4%/30.8% of patients. PS-adjusted odds ratios (OR; 95% confidence interval (CI)) of reaching cDAPSA LDA and MDA were 0.73 (0.46 to 1.15) and 0.87 (0.61 to 1.25) with ustekinumab versus TNFi, indicating no significant difference. High baseline body mass index or high cDAPSA were associated with a lower chance (OR (95% CI)) of reaching cDAPSA LDA with TNFi (0.94 (0.89 to 0.99) and 0.64 (0.52 to 0.79), respectively). Predictive factors were similar to previously published evidence, with cDAPSA and 12-item Psoriatic Arthritis Impact of Disease scores and chronic widespread pain at baseline appearing as new risk factors for unfavourable outcome. Safety data were similar between groups. CONCLUSION: Treatment targets were reached similarly after 6 months of treatment with ustekinumab and TNFi.

Evaluation of Psoriasis Area and Severity Index as a Proxy for Bio-markers of Systemic Disease under Treatment with Tumour Necrosis Factor-alpha and Interleukin 12/23 Antagonists in Patients with Psoriasis: A Retrospective Cohort Study of 186 Treatment Cycles.

The efficacy of psoriasis treatments is usually evaluated using the Psoriasis Area and Severity Index (PASI). However, there is a lack of systematic statistical assessments of PASI as a proxy for systemic disease in individual patients. Therefore, a retrospective study of 186 treat-ments with adalimumab, etanercept, and ustekinumab for psoriasis (341 patient-years) was performed. While PASI significantly and independently correlated with biomarkers of systemic inflammation (especially neutrophil-to-lymphocyte ratio, C-reactive protein), the strengths were only weak-to-moderate and varied considerably inter-individually. A decrease in PASI indicated a neutrophil-to-lymphocyte ratio decrease and a C-reactive protein decrease or stable low margin C-reactive protein in ≥ 80%. Sensitivity, specificity, and positive predictive value of PASI 0 and PASI 2.75 (optimal Youden Index) for low cardiovascular risk C-reactive protein were 24%, 92%, 85%, and 62%, 61%, 76%, respectively. Performance was similar using absolute thresholds and PASI 100 or PASI 75, and overall worse for low cardiovascular risk neutrophil-to-lympho-cyte ratio and if psoriasis arthritis was present. In conclusion, PASI allows robust low-order estimates of systemic inflammation, but cannot substitute for laboratory biomarkers for more precise assessments.

Drug Survival of IL-12/23, IL-17 and IL-23 Inhibitors for Psoriasis Treatment: A Retrospective Multi-Country, Multicentric Cohort Study.

BACKGROUND: Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis-ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab-and to identify clinical predictors that can influence the drug survival of these drugs. METHODS: This retrospective multicentric cohort study from 16 dermatology centers in Portugal, Spain, Italy, Switzerland, Czech Republic, Canada, and the United States included patients that started IL-12/23, IL-17 (IL-17A and IL-17R) and IL-23 inhibitors for the treatment of psoriasis between January 1, 2012 and December 31, 2019. Survival analysis was performed using a Kaplan-Meier estimator, to obtain descriptive survival curves, and proportional hazard Cox regression models. RESULTS: A total of 3312 treatment courses (total patients: 3145) were included in the study; 1118 (33.8%) with an IL-12/23 inhibitor (ustekinumab), 1678 (50.7%) with an IL-17 inhibitor [911 (27.5%) on secukinumab, 651 (19.7%) on ixekizumab, 116 (3.5%) on brodalumab], and 516 (15.5%) with an IL-23 inhibitor [398 (12.0%) on guselkumab, 118 (3.5%) on risankizumab]. At 18 months, the cumulative probability of survival was 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab. Using ustekinumab as reference, drug survival of guselkumab was higher (HR 0.609; 95% CI 0.418-0.887) and that of secukinumab was lower (HR 1.490; 95% CI 1.257-1.766). In the final multivariable model, secukinumab, female sex, higher BMI, and prior exposure to biologic agents significantly increased the risk of drug discontinuation, whereas risankizumab was protective. CONCLUSION: In this multinational cohort with 8439 patient-years of follow-up, the cumulative probability of drug survival for all drugs was >79% at 18 months. Prescribed biologic, female sex, higher BMI, and previous exposure to biologic agents were predictors of drug discontinuation. Drug survival of guselkumab and risankizumab was higher than that of ustekinumab, and secukinumab was lower.

Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity.

The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.

Clinical phenotypes and therapeutic responses in cutaneous-predominant sarcoidosis: 6-year experience in a tertiary referral service.

BACKGROUND: There is a limited evidence base for the treatment of cutaneous sarcoidosis. OBJECTIVE: To describe treatment modalities and responses in patients with predominantly cutaneous sarcoidosis, in addition to clinical characteristics and prevalence of systemic disease. METHODS: Data were prospectively collected over a 6-year period. The Cutaneous Sarcoidosis Activity and Morphology Index was used to assess treatment effectiveness. RESULTS: In total, 47 patients with biopsy-confirmed cutaneous sarcoidosis were identified. Morphologically, the most common lesions were papules (49%) and plaques (42.6%). The most commonly affected sites were the head and neck (79%); 89.4% had systemic as well as cutaneous disease; 77% received systemic corticosteroid therapy, while 87% required further steroid-sparing treatment; 40% achieved clinical remission with hydroxychloroquine (HCQ) and 88% achieved clinical remission with methotrexate (MTX). OR of achieving remission on MTX compared with HCQ was 9.8 (95% CI 2.4-40.4, P = 0.001). MTX was superior to both azathioprine (AZA) (OR = 22; 95% CI 1.7-285.9; P = 0.02) and mycophenolate mofetil (MMF) (OR = 22; 95% CI 1.7-285.9; P = 0.02) in achieving remission. CONCLUSION: HCQ is effective and well-tolerated. MTX was associated with significantly increased probability of achieving clinical remission compared with AZA and MMF.

Inhibition of inflammatory cytokine production and proliferation in macrophages by Kunitz-type inhibitors from Echinococcus granulosus.

The genus Echinococcus of cestode parasites includes important pathogens of humans and livestock animals. Transcriptomic and genomic studies on E. granulosus and E. multilocularis uncovered striking expansion of monodomain Kunitz proteins. This expansion is accompanied by the specialization of some family members away from the ancestral protease inhibition function to fulfill cation channel blockade functions. Since cation channels are involved in immune processes, we tested the effects on macrophage physiology of two E. granulosus Kunitz-type inhibitors of voltage-activated cation channels (Kv) that are close paralogs. Both inhibitors, EgKU-1 and EgKU-4, inhibited production of the Th1/Th17 cytokine subunit IL-12/23p40 by macrophages stimulated with the TLR4 agonist LPS. In addition, EgKU-4 but not EgKU-1 inhibited production of the inflammatory cytokine IL-6. These activities were not displayed by EgKU-3, a family member that is a protease inhibitor without known activity on cation channels. EgKU-4 potently inhibited macrophage proliferation in response to M-CSF, whereas EgKU-1 displayed similar activity but with much lower potency, similar to EgKU-3. We discuss structural differences, including a heavily cationic C-terminal extension present in EgKU-4 but not in EgKU-1, that may explain the differential activities of the two close paralogs.

Linarin Protects the Kidney against Ischemia/Reperfusion Injury via the Inhibition of Bioactive ETS2/IL-12.

Ischemia/reperfusion injury (IRI), a participant in acute kidney injury (AKI), can occur as a series of pathological processes such as inflammation. Linarin (LIN) has been widely used for different diseases. To confirm the anti-inflammatory value and relevant mechanism of LIN during IRI, in vivo and vitro models were established. LIN or dissolvent was given, and histologic analysis, quantitative (q)RT-PCR, serum creatinine and blood urea nitrogen testing were used to evaluate kidney injury. Microarray analysis, protein-protein interaction (PPI) analysis and molecular docking were used to identify the target protein of LIN, and small interfering RNA (siRNA) transfection was applied to explore the crucial role of identified protein. First, we found that LIN inhibited kidney injury in an in vivo IRI model and decreased the expression of interleukin-12 (IL-12) p40 in vivo and in vitro IRI models. To explore the mechanism of LIN, we collected raw data from a public microarray database and identified E26 oncogene homolog 2 (ETS2) as a crucial protein of LIN according to microarray analysis and PPI. Meanwhile, qRT-PCR indicated that IL-12 p40 showed no significant difference between ETS2 knock down group and LIN treated ETS2 knock down group after hypoxia reoxygenation treatment. In addition, according to molecular docking the contact area is highly conserved and located on a PPI domain of ETS2 which indicates that LIN may alter the interaction with synergistic proteins in the regulation of IL-12 p40 expression. Our study demonstrated the anti-inflammatory effect of LIN during IRI-AKI, broadening the medicinal value of LIN and the therapeutic options for IRI-AKI.

Medical therapy versus surgery in moderate-to-severe ulcerative colitis.

Ulcerative colitis, a chronic inflammatory condition that affects the colon from rectum to caecum, is characterized by periods of increased bowel movements, blood in feces, rectal urgency, tenesmus, and abdominal pain, with periods of remission and flares of disease, which negatively impact quality of life. A number of therapeutic options are available for patients with moderate-to-severe ulcerative colitis, however, no clear treatment algorithm exists. Therapeutic goals include short-term benefits for patients (i.e., the reduction/absence of symptoms, essentially stool frequency and rectal bleeding) and long-term benefits (i.e., sustained clinical remission, steroid-free remission, and mucosal healing). Therapies currently approved and available for the treatment of moderate-to-severe ulcerative colitis include monoclonal antibodies such as those targeting anti-tumor necrosis factor α (i.e., infliximab, adalimumab, golimumab), anti-adhesion molecules (i.e., vedolizumab), anti-interleukin 12/23 agents (i.e., ustekinumab), and Janus Kinase inhibitors (i.e., tofacitinib). Surgical approaches should also be considered in patients refractory to medical therapy or with complications (including toxic megacolon or colonic dysplasia/cancer). This review provides an overview of currently available treatment options for patients with moderate-to-severe ulcerative colitis and summarizes factors that should be considered during the therapeutic decision.

The risk of respiratory tract infections and interstitial lung disease with interleukin 12/23 and interleukin 23 antagonists in patients with autoimmune diseases: A systematic review and meta-analysis.

BACKGROUND: Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL) 12/23 or IL-23 antagonists have been reported in autoimmune diseases. OBJECTIVE: To assess the risk of RTIs and noninfectious ILD with these drugs. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials. Risk of RTIs and noninfectious ILD was compared to placebo by Mantel-Haenszel risk difference. We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Noninfectious ILD included ILD, eosinophilic pneumonia, and pneumonitis. RESULTS: We identified 54 randomized controlled trials including 10,907 patients with 6 IL-12/23 or IL-23 antagonists and 5175 patients with placebo. These drugs significantly increased the risk of RTIs (Mantel-Haenszel risk difference, 0.019; 95% confidence interval, 0.005-0.033; P = .007), which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and noninfectious ILD between 2 groups. LIMITATIONS: Because of the rarity of infectious pneumonia and ILD, sensitivity analysis was required. CONCLUSIONS: The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and noninfectious ILD.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update.

OBJECTIVE: To update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA). METHODS: According to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined. RESULTS: The updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed. CONCLUSION: These recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.