The repeated administration of rhIL-12 for 14 weeks in rhesus monkeys: A toxicity assessment.

Interleukin-12 (IL-12) is known to exert antitumor immune effects by promoting the activation and proliferation of T cells and NK cells within the immune system. However, clinical trials have observed systemic toxicity associated with the administration of IL-12. This has shelved development plans for its use as a cancer therapeutic drug. Therefore, it is critical that we perform a systematic evaluation of the toxicity and safety of repeated IL-12 administration. In this study, we conducted a comprehensive evaluation of the toxicity and safety of repeated rhIL-12 (recombinant human interleukin-12) administration in rhesus monkeys by assessing its effects on the immune system, organ function, and vital signs. Rhesus monkeys were subcutaneously injected with 0.5, 2.5, and 12.5 µg/kg of rhIL-12 for up to for 14 consecutive weeks. The low dose exhibited no signs of toxicity, whereas animals receiving higher doses displayed symptoms such as loose stools, reduced activity, anemia, and elevated liver function indicators (AST and TBIL). Following three administrations of 12.5 µg/kg, high dosing was adjusted to 7.5 µg/kg due to manifestations of symptoms like loose stools, decreased activity, and huddling in the cage. Furthermore, rhesus monkeys exhibited marked immunogenic responses to recombinant human interleukin-12 (rhIL-12). However, based on overall study findings, the No Observed Adverse Effect Level (NOAEL) for the subcutaneous injection of rhIL-12, when repeatedly administered for 3 months in rhesus monkeys, was considered to be 0.5 µg/kg. The Highest Non-Severely Toxic Dose (HNSTD) was considered to be 7.5 µg/kg.

Higher Ustekinumab Levels in Maintenance Therapy are Associated with Greater Mucosal Healing and Mucosal Response in Crohn's Disease: An Experience of 2 IBD Centers.

BACKGROUND: Ustekinumab (UST), a human monoclonal antibody that binds the p40 subunit of interleukin 12 (IL-12) and IL-23, is licensed for induction and maintenance therapy of moderate to severe inflammatory bowel disease (IBD). To date, there is limited data published on any potential association between ustekinumab serum trough levels and mucosal healing in order to guide treatment strategies and appropriate dosing. AIM: This study aims to identify a relationship between maintenance ustekinumab serum trough levels and mucosal healing and/or response in patients with Crohn's disease in an observational cohort study. METHODS: Ustekinumab serum trough levels and antibody titres were analyzed in patients on maintenance drug using an ELISA drug-tolerant assay. Mucosal response (MR) was defined as ≥50% reduction in fecal calprotectin level (FC) and/or ≥50% reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD score). Mucosal healing (MH) was defined as FC ≤150 µg/mL and/or global SES-CD score ≤5. Median trough levels were analyzed using the Kruskal-Wallis test, and logistic regression was used to determine sensitivity and specificity of levels predicting mucosal response. RESULTS: Forty-seven patients on maintenance ustekinumab for Crohn's disease were included in this study. The majority were female (66%), with a median age of 40 years (21-78 years). The majority of patients were biologic-experienced (89.4%, n = 42). Patients with histologically confirmed Crohn's disease represented 100% (n = 47) of the cohort. Over one-third of patients (n = 18, 38.3%) were on higher than standard dosing of 90 mg every 8 weeks. Patients with mucosal healing (n = 30) had significantly higher mean serum ustekinumab levels (5.7 µg/mL, SD 6.4) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). A serum ustekinumab trough level greater than 2.3 µg/mL was associated with MH, with a sensitivity of 100% and specificity of 90.6% (likelihood ratio 10.7). Similarly, for patients with MR (n = 40), we observed a higher mean serum ustekinumab trough level (5.1 µg/mL, SD 6.1) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). Furthermore, a serum ustekinumab trough level greater than 2.3 µg/mL was associated with a 10-fold increased likelihood of mucosal response vs mucosal nonresponse (sensitivity 100%, specificity 90.5%, likelihood ratio 10.5). CONCLUSION: This study demonstrates that higher ustekinumab serum trough levels are associated with a greater likelihood of achieving mucosal healing and mucosal response in patients with Crohn's disease regardless of prior biologic exposure. Further prospective studies are required to correlate target maintenance trough levels and the optimal time to dose-escalate in order to improve patient outcomes.

Non-Invasive Assessment of Skin Surface Proteins of Psoriasis Vulgaris Patients in Response to Biological Therapy.

Measurements of skin surface biomarkers have enormous value for the detailed assessment of skin conditions, both for clinical application and in skin care. The main goals of the current study were to assess whether expression patterns of skin surface hBD-1, hBD-2, IL-1α, CXCL-1, and CXCL-8, examples of proteins known to be involved in psoriasis pathology, are associated with disease severity and whether expression patterns of these proteins on the skin surface can be used to measure pharmacodynamic effects of biological therapy. In this observational study using transdermal analysis patch (TAP), levels of skin surface IL-1α, hBD-1, hBD-2, CXCL-1/2, and CXCL-8 of psoriasis vulgaris (PV) patients over biological therapy were assessed. The Psoriasis Area Severity Index (PASI) and local score for erythema, induration, and desquamation were determined from the exact same skin area as FibroTx TAP measurements. Thirty-seven adult PV patients were included, of which twenty-three were subjected to anti-TNF-α, seven to anti-IL-17A, and seven to anti-IL12/IL-23 therapy. Significantly higher levels of hBD-1, hBD-2, CXCL-1/2, and CXCL-8 were detected on lesional skin compared to the non-lesional skin of the PV patients. In contrast, lower levels of IL-1α were found in lesional skin compared to non-lesional skin. In addition, we observed that the biomarker expression levels correlate with disease severity. Further, we confirmed that changes in the expression levels of skin surface biomarkers during biological therapy correlate with treatment response. Biomarker expression patterns in response to treatment differed somewhat between treatment subtypes. We observed that, in the case of anti-TNF-α therapy, an increase after a steady decrease in the expression levels of CXCL-1/2 and CXCL-8 occurred before the change in clinical scores. Moreover, response kinetics of skin surface proteins differs between the applied therapies-hBD2 expression responds quickly to anti-IL-17A therapy, CXCL-1/2 to anti-IL-12/23, and levels of CXCL-8 are rapidly down-regulated by IL-17A and IL-12/23 therapy. Our findings confirm that the skin surface hBD-2, IL-1α, CXCL-1/2, and CXCL-8 are markers for the psoriasis severity. Further, data obtained during this study give the basis for the conclusion that skin surface proteins CXCL-1/2 and CXCL-8 may have value as therapeutic biomarkers, thus confirming that measuring the 'molecular root' of inflammation appears to have value in scoring disease severity on its own.

Persistence of second-line biologics in psoriasis after first-line biologic failure: a nationwide cohort study from the French health insurance database (SNDS).

BACKGROUND: Many biologics are available for psoriasis and have been compared in real-life studies based on their persistence (i.e. time between initiation and discontinuation). However, after first-line biologic failure, data are lacking on the choice of second-line biologic among the four available classes [tumour necrosis factor inhibitors (TNFi); interleukin (IL)-12/IL-23 inhibitor (IL-12/IL-23i); IL-17 inhibitors (IL-17i); and IL-23 inhibitors (IL-23i)]. OBJECTIVES: To compare the long-term persistence of available second-line biologics in psoriasis according to prior exposure. METHODS: This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to a hospital discharge database. Participants were adults with psoriasis, defined as having at least two prescriptions of a topical vitamin D derivative within a 2-year period, with initiation of a second-line biologic between 1 January 2015 and 31 December 2021. We included patients who initiated a second-line biologic directly after first-line discontinuation (i.e. without a 'washout' period). The end of follow-up was 30 June 2022. Discontinuation was defined as > 90 days without filling a prescription for the same treatment after the period covered by the previous prescription. Comparison of persistence by biologic class involved using propensity score-weighted Cox models (inverse probability treatment weighting) and adjustment of specific systemic nonbiologics (time-dependent variables). RESULTS: We included 8693 patients [mean (SD) age 50 (14) years; 50.5% male]; 2824 (32.5%) started TNFi, 1561 (18.0%) IL-12/IL-23i, 2707 (31.1%) IL-17i and 1601 (18.4%) IL-23i. Overall, 1- and 3-year persistence rates were 60% and 30%, respectively. After weighting and adjustment, persistence was longer with IL-12/IL-23i [weighted hazard ratio (HRw) 0.68, 95% confidence interval (CI) 0.62-0.76)], IL-17i (HRw 0.70, 95% CI 0.64-0.78) and IL-23i (HRw 0.36, 95% CI 0.31-0.42) than TNFi, except after first-line IL-17i treatment, with no difference between IL-12/IL-23i, IL-17i and TNFi second-line persistence. Persistence was longer with IL-23i as a second-line treatment than IL-12/IL-23i (HRw 0.53, 95% CI 0.44-0.63) and IL-17i (HRw 0.51, 95% CI 0.44-0.60), regardless of first-line treatment, with no difference seen between IL-12/IL-23i and IL-17i (HRw 0.97, 95% CI 0.87-1.09). CONCLUSIONS: This real-life study suggests the longer persistence of IL-23i than TNFi, IL-17i and IL-12/IL-23i as second-line treatment for psoriasis. Persistence rates for all biologics remained low at 3 years.

Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use.

Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.

Potential of Interleukin (IL)-12 Group as Antivirals: Severe Viral Disease Prevention and Management.

The interleukin (IL)-12 family consists of pro- and anti-inflammatory cytokines that are able to signal the activation of host antiviral immunity while preventing over-reactive immune reactions due to active virus replication and viral clearance. Amongst others, IL-12 and IL-23 are produced and released by innate immune cells such as monocytes and macrophages to signal the proliferation of T cells and release of effector cytokines, which subsequently activate host defence against virus infections. Interestingly, the dualities of IL-27 and -35 are evidently shown in the course of virus infections; they regulate the synthesis of cytokines and antiviral molecules, proliferation of T cells, and viral antigen presentation in order to maximize virus clearance by the host immune system. In terms of anti-inflammatory reactions, IL-27 signals the formation of regulatory T cells (Treg) which in turn secrete IL-35 to control the scale of inflammatory response that takes place during virus infections. Given the multitasking of the IL-12 family in regards to the elimination of virus infections, its potential in antiviral therapy is unequivocally important. Thus, this work aims to delve deeper into the antiviral actions of the IL-12 family and their applications in antiviral therapies.

Multiple Cytokine Analysis of Th1/Th2/Th9/Th17/Th22/Treg Cytokine Pathway for Individual Immune Profile Assessment in Patients with Psoriasis.

BACKGROUND Psoriasis is an autoimmune and autoinflammatory disorder that has a significant impact on patient quality of life. The aim of the study was to assess the immune profiles of patients with psoriasis with multiple cytokine analysis. MATERIAL AND METHODS Fifty-two male psoriatic patients and 24 healthy male volunteers were recruited. Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), interleukin (IL)-1 beta, IL-2, Il-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-21, IL-22, IL-23, IL-27, and tumor necrosis factor (TNF)-alpha were measured in patients' serum with a Th1/Th2/Th9/Th17/Th22/Treg Cytokine 18-Plex Human ProcartaPlex Panel, based on Luminex xMAP technology. RESULTS The median fluorescence intensities of serum GM-CSF, IL-2, IL-5, IL-10, IL-13, IL-17A, IL-21, and IL-22 were not intensive enough to calculate the cytokine concentration. We observed elevated levels of IL-6 (P=0.001) and IL-9 (P=0.003) in patients, compared with the control group. The levels of IL-1beta (P=0.008) and IL-27 (P=0.006) were decreased. In patients with psoriatic arthritis, we noticed a decreased level of IL-9 compared with that in patients without arthritis (P=0.034). The levels of IL-12 (P<0.05) and IL-18 (P<0.05) correlated positively with the Psoriasis Area and Severity Index. We found negative correlations of IL-9 (P<0.05), IL-12 (P<0.05), and IL-23 (P<0.05) with the age of psoriatic patients; IL-12 (P<0.05) and IL-23 (P<0.05) with psoriasis duration; and IL-6 (P<0.05) and IL-9 (P<0.05) with the Nail Psoriasis Severity Index. CONCLUSIONS Multiple cytokine analysis seems to be an important form of individual immune profile assessment before treatment selection.

Comparative assessment of the mouse immune responses to colistin-resistant and colistin-sensitive isolates of Acinetobacter baumannii.

Acinetobacter baumannii is known as the most frequent species in clinical samples that is responsible for a large number of nosocomial infection outbreaks. The colistin-resistance of this bacterium has been found to be increasing. This study aimed to evaluate the immune response to colistin-susceptible and colistin-resistant A. baumannii isolates in a mouse model. Samples were prepared from the wounds of patients suspected of A. baumannii admitted to the intensive care unit of Namazi Hospital in Shiraz. Antibiotic susceptibility was studied by disk diffusion and broth microdilution according to CLSI and EUCAST criteria. Among the isolates, one colistin-sensitive isolate and one colistin-resistant isolate were injected intraperitoneally to BALB/C mice. Blood samples were collected after 4 h and cytokines (IL1-ß, IL-12, IFN γ, and IL-10) and surface markers (CD4, CD8, CD3, and CD45) were determined by ELISA and flow cytometry. Then, hematologic and histopathological factors were analyzed, and colony count in lung, liver, kidney, and spleen tissues were also performed. The results showed that levels of cytokines (IL1-ß, IL-12, IFN γ, and IL-10) and markers (CD4, CD8, CD3 and CD45) were higher in mice receiving colistin-resistant A. baumannii isolates than in mice receiving colistin-sensitive A. baumannii isolates, indicating that colistin-resistant isolates 4 h following the intraperitoneal injection stimulated host innate immune system better and produced a stronger immune response. On the other hand, histopathological findings showed inflammatory cell infiltration, hyperemia, and tissue damage. In addition, the bacterial load and tissue damage in the lung was higher than other tissues. The results of this study can have promising potential for the development of a prevention and treatment strategy based on cellular immune response for infection caused by colistin-sensitive and colistin-resistant A. baumannii.

Long-term Persistence of First-line Biologics for Patients With Psoriasis and Psoriatic Arthritis in the French Health Insurance Database.

Importance: Treatment options for psoriasis (PsO) and psoriatic arthritis (PsA) have evolved significantly throughout the era of biologics. Clinical trials are inadequate to assess the relative long-term efficacy of biologics and are often insufficient regarding safety. Objectives: To assess the long-term persistence of different biologic classes to treat PsO and PsA. Design, Setting, and Participants: This nationwide cohort study involved the administrative health care database of the French health insurance scheme linked to the hospital discharge database. All adults with PsO and PsA who were new users of biologics (not in the year before the index date) from January 1, 2015, to May 31, 2019, were included and followed up through December 31, 2019. Patients hospitalized for PsA in the PsO cohort and for PsO in the PsA cohort in the year before the index date were excluded. Data were analyzed from June 1 to October 31, 2021. Main Outcomes and Measures: Persistence was defined as the time from biologic therapy initiation to discontinuation and was estimated using the Kaplan-Meier method. Comparison of persistence by biologic class involved using propensity score-weighted Cox proportional hazards regression models and adjustment on specific systemic nonbiologics (time-dependent variables). Results: A total of 16 892 patients with PsO were included in the analysis (mean [SD] age, 48.5 [13.8] years; 9152 men [54.2%] men). Of these, 10 199 patients (60.4%) started therapy with a tumor necrosis factor (TNF) inhibitor; 3982 (23.6%), with an interleukin 12 and interleukin 23 (IL-12/23) inhibitor; and 2711 (16.0%), with an interleukin 17 (IL-17) inhibitor. An additional 6531 patients with PsA (mean [SD] age, 49.1 [12.8] years; 3565 [54.6%] women) were included; of these, 4974 (76.2%) started therapy with a TNF inhibitor; 803 (12.3%), with an IL-12/23 inhibitor; and 754 (11.5%), with an IL-17 inhibitor. Overall 3-year persistence rates were 40.9% and 36.2% for PsO and PsA, respectively. After inverse probability of treatment weighting and adjustment, the IL-17 inhibitor was associated with higher persistence compared with the TNF inhibitor for PsO (weighted hazard ratio [HR], 0.78 [95% CI, 0.73-0.83]) and PsA (weighted HR, 0.70 [95% CI, 0.58-0.85]) and compared with the IL-12/23 inhibitor for PsA (weighted HR, 0.69 [95% CI, 0.55-0.87]). No difference between the IL-17 inhibitor and IL-12/23 inhibitor for PsO was noted. The IL-12/23 inhibitor was associated with higher persistence than the TNF inhibitor for PsO (weighted HR, 0.76 [95% CI, 0.72-0.80]), with no difference observed for PsA. Conclusions and Relevance: The findings of this cohort study suggest that IL-17 inhibitors are associated with higher treatment persistence than the TNF inhibitor for PsO and PsA. Interleukin 17 inhibitors were also associated with higher persistence than the IL-12/23 inhibitor for PsA, with no difference for PsO. However, the persistence rates of all biologics remained globally low at 3 years.

Long-term persistence of second-line biologics in psoriatic arthritis patients with prior TNF inhibitor exposure: a nationwide cohort study from the French health insurance database (SNDS).

INTRODUCTION: Tumour necrosis factor inhibitor (TNFi) agents are most often the first-choice biological treatment for patients with psoriatic arthritis (PsA). When their discontinuation is needed, a switch to another TNFi or to another therapeutic class may be considered. However, data supporting one approach over another are lacking. OBJECTIVE: To compare the long-term persistence of classes of biologics in PsA patients with prior TNFi exposure. METHODS: This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database. We included all adults with PsA starting a second-line biological after discontinuing a TNFi during 2015-2020. Persistence was defined as the time from biological initiation to discontinuation and was estimated by the Kaplan-Meier method. Comparison of persistence by biological class was performed with Poisson regression models with time divided into 6-month intervals. RESULTS: We included 2975 patients: 1580 (53%) initiating a second TNFi, 426 (14%) an interleukin 12/23 inhibitor (IL-12/23i) and 969 (33%) an IL-17 inhibitor (IL-17i). Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively. After adjustment, persistence was associated with treatment with an IL-17i (adjusted relative risk (RRa) 0.79, 95% CI 0.71 to 0.87) or IL-12/23i (RRa 0.69, 95% CI 0.61 to 0.79) vs a TNFi, with no significant difference between IL-12/23 and IL-17 inhibitors (RRa 0.88, 95% CI 0.76 to 1.02). CONCLUSIONS: Overall, this real-life study shows low persistence for all biologics at 3 years in PsA patients previously exposed to a TNFi. However, persistence was higher with an IL-17i or IL-12/23i than a TNFi.

Assessment of Th1/Th2 cytokines among patients with Middle East respiratory syndrome coronavirus infection.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a member of the beta-coronavirus genus of zoonotic origin that emerged in the Arabian Peninsula and is associated with significant morbidity and mortality. This study was conducted to assess the plasma levels of cytokines to evaluate the Th1/Th2 status among 46 MERS-CoV-infected patients (19 asymptomatic and 27 symptomatic) and 52 normal healthy controls using a customized luminex kit. Comparative analysis of data between MERS-CoV-infected patients and normal healthy controls revealed that although no difference was observed between asymptomatic MERS-CoV patients and controls, the mean plasma levels of interleukin (IL)-10 (44.69 ± 40.04 pg ml-1 versus 14.84 ± 6.96 pg ml-1; P < 0.0001), IL-4 (22.46 ± 8.02 pg ml-1 versus 16.01 ± 9.97 pg ml-1; P < 0.0001), IL-5 (10.78 ± 2.86 pg ml-1 versus 8.06 ± 1.41 pg ml-1; P < 0.0001) and IL-13 (14.51 ± 3.97 pg ml-1 versus 11.53 ± 4.16 pg ml-1; P < 0.003) in MERS-CoV symptomatic patients were significantly higher than the normal controls. The mean plasma levels of interferon (IFN)-γ and IL-12 were no different among the study groups. The cytokine profile among symptomatic MERS-CoV-infected patients was skewed to a Th2 type immune response.

Autologous Whole-blood Injections in Chronic Spontaneous Urticaria: Assessment of Efficacy Biomarkers.

No abstract.

Dose Escalation Assessment Among Targeted Immunomodulators in the Management of Inflammatory Bowel Disease.

BACKGROUND: The need for individualized treatment regimens is becoming more important in the management of patients with inflammatory bowel disease (IBD). Gastroenterologists may dose adjust either by increasing the dose or shortening the dosing interval from the initial recommended maintenance dose to achieve an appropriate clinical response. Understanding the role of dose escalation in the treatment of IBD in clinical practice provides payers in the United States insight into the real-world cost-effectiveness of targeted immunomodulators (TIMs) in the management of IBD. OBJECTIVE: To assess the prevalence and magnitude of dose escalation for approved IBD therapies. METHODS: Using the Source Healthcare Analytics database, patients with IBD who initiated treatment with a drug of interest from July 2015 to June 2017 were identified. Patient utilization of the TIMs was tracked for 12 months following initiation. All included patients had at least 2 diagnoses for ulcerative colitis or Crohn disease before TIM initiation and at least 5 claims for a drug of interest within the 12 months following initiation. Dose escalation was defined as an increase of at least 30% in the average daily dose (ADD) relative to the patient's expected maintenance dose on 2 consecutive prescriptions. The proportion of patients with dose escalation in the first 12 months after treatment initiation was determined. The magnitude of dose escalation was determined by calculating the patient's ADD across all noninduction dose claims and comparing it with the expected daily dose. Dose escalation prevalence and magnitude were used to quantify the equivalent patient treatment rate representing the number of patients per 100 that could have been treated with standard dosing, given the prevalence of dose escalation in the treated population. RESULTS: 7,028 patients (2,406 infliximab, 1,966 adalimumab, 1,745 vedolizumab, 472 ustekinumab, 285 certolizumab pegol, and 154 golimumab) met eligibility criteria and were included in the study. Among IBD therapies, dose escalation occurred most frequently with infliximab (39%), followed by adalimumab (28%), vedolizumab (23%), ustekinumab (22%), certolizumab pegol (20%), and golimumab (14%). The magnitude of dose escalation was greatest for ustekinumab (131%), followed by infliximab (70%), vedolizumab (62%), adalimumab (59%), certolizumab pegol (50%), and golimumab (45%). The calculated patient equivalence was highest for infliximab (128) and ustekinumab (128) compared with adalimumab (116), vedolizumab (114), certolizumab pegol (110), and golimumab (106). CONCLUSIONS: Among patients with IBD, dose escalation occurred with all TIMs examined with varying degrees of prevalence and magnitude. Real-world utilization patterns of TIMs indicate that dose escalation is an important part of the clinical management of IBD and needs to be considered when evaluating the cost-effectiveness of IBD treatments. DISCLOSURES: Financial support for this study was provided by AbbVie, which participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Ehrenberg and McDonald are employees of IQVIA, which received funding from AbbVie to participate in this research. Griffith and Theigs are employed by AbbVie and may own stock or stock options in AbbVie.

Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis.

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.

Characterization of disease burden, comorbidities, and treatment use in a large, US-based cohort: Results from the Corrona Psoriasis Registry.

BACKGROUND: Psoriasis is an immunodysregulatory inflammatory disease associated with comorbidities affecting quality of life. With the advent of new treatments, there is growing need to assess the long-term safety and efficacy of treatments in a real-world setting. OBJECTIVE: The objective of the Corrona Psoriasis Registry is to study the comparative safety and efficacy of Food and Drug Administration-approved biologic treatments. METHODS: A cross-sectional study of patients enrolled in the registry, who initiated or switched to a systemic therapy at enrollment or previous 12 months. Descriptive characteristics (demographics, clinical and patient-reported outcomes, comorbidities, and treatment history) were examined at registry enrollment. RESULTS: As of October 1, 2016, there were 1942 patients enrolled in the registry: 23% on apremilast, 4% on other nonbiologic systemic medications, 25% on interleukin (IL) 17A inhibitors, 22% on an IL-12/23 inhibitor, and 26% on tumor necrosis factor inhibitors. Overall, mean disease duration was 15.6 years, and 40% had a concurrent psoriatic arthritis diagnosis. About 66% had >3% body surface area involvement and 49% had a moderate or severe Investigator Global Assessment. LIMITATIONS: Selection and channeling bias can result in potential confounding that needs to be addressed in modeled analyses. CONCLUSION: This disease-based registry cohort represents a population exposed to multiple therapies, long disease duration, and multiple comorbidities and can be used to examine comparative safety and efficacy of various therapies.

In vitro assessment of the ability of probiotics, blueberry and food carbohydrates to prevent S. pyogenes adhesion on pharyngeal epithelium and modulate immune responses.

Group A streptococci (GAS) cause 20-30% of pediatric pharyngitis episodes, which are a major cause of ambulatory care visits. Therefore, a strategy to prevent GAS dissemination in children could significantly benefit public healthcare. Contextually, we assessed the possibility of employing alternative food-grade strategies to be used with the oral probiotic L. helveticus MIMLh5 for the prevention of pharyngeal infections. First, we demonstrated through an antagonism-by-exclusion assay that guaran may potentially prevent S. pyogenes adhesion on pharyngeal cells. Subsequently, we showed that an anthocyanin-rich fraction extracted from wild blueberry (BbE) exerts anti-inflammatory effects on the human macrophage cell line U937. Finally, we showed that BbE reduces interferon-ß expression in MIMLh5-stimulated murine dendritic cells, resulting in a reduction in the pro-inflammatory cytokines IL-12 and TNF-α. In conclusion, this proof-of-concept study indicates that different food-grade strategies may be concomitantly adopted to potentially prevent GAS colonization and modulate local immune defences.

Assessment of sesquiterpene lactones isolated from Mikania plants species for their potential efficacy against Trypanosoma cruzi and Leishmania sp.

Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts. Mikanolide and deoxymikanolide were the major compounds in both extracts (2.2% and 0.4% for Mikania variifolia and 21.0% and 6.4% for Mikania micrantha respectively, calculated on extract dry weight). Mikanolide, deoxymikanolide and dihydromikanolide were active against Trypanosoma cruzi epimastigotes (50% inhibitory concentrations of 0.7, 0.08 and 2.5 µg/mL, for each compound respectively). These sesquiterpene lactones were also active against the bloodstream trypomastigotes (50% inhibitory concentrations for each compound were 2.1, 1.5 and 0.3 µg/mL, respectively) and against amastigotes (50% inhibitory concentrations for each compound were 4.5, 6.3 and 8.5 µg/mL, respectively). By contrast, scandenolide was not active on Trypanosoma cruzi. Besides, mikanolide and deoxymikanolide were also active on Leishmania braziliensis promastigotes (50% inhibitory concentrations of 5.1 and 11.5 µg/mL, respectively). The four sesquiterpene lactones were tested for their cytotoxicity on THP 1 cells. Deoxymikanolide presented the highest selectivity index for trypomastigotes (SI = 54) and amastigotes (SI = 12.5). In an in vivo model of Trypanosoma cruzi infection, deoxymikanolide was able to decrease the parasitemia and the weight loss associated to the acute phase of the parasite infection. More importantly, while 100% of control mice died by day 22 after receiving a lethal T. cruzi infection, 70% of deoxymikanolide-treated mice survived. We also observed that this compound increased TNF-α and IL-12 production by macrophages, which could contribute to control T. cruzi infection.

Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry.

Sarcoidosis is a complex disease of unknown etiology characterized by the presence of granulomatous inflammation. Though various immune system pathways have been implicated in disease, the relationship between the genetic determinants of sarcoidosis and other inflammatory disorders has not been characterized. Herein, we examined the degree of genetic pleiotropy common to sarcoidosis and other inflammatory disorders to identify shared pathways and disease systems pertinent to sarcoidosis onset. To achieve this, we quantify the association of common variant polygenic risk scores from nine complex inflammatory disorders with sarcoidosis risk. Enrichment analyses of genes implicated in pleiotropic associations were further used to elucidate candidate pathways. In European-Americans, we identify significant pleiotropy between risk of sarcoidosis and risk of asthma (R2=2.03%; P=8.89 × 10-9), celiac disease (R2=2.03%; P=8.21 × 10-9), primary biliary cirrhosis (R2=2.43%; P=2.01 × 10-10) and rheumatoid arthritis (R2=4.32%; P=2.50 × 10-17). These associations validate in African Americans only after accounting for the proportion of genome-wide European ancestry, where we demonstrate similar effects of polygenic risk for African-Americans with the highest levels of European ancestry. Variants and genes implicated in European-American pleiotropic associations were enriched for pathways involving interleukin-12, interleukin-27 and cell adhesion molecules, corroborating the hypothesized immunopathogenesis of disease.

Strategies for serum chemokine/cytokine assessment as biomarkers of therapeutic response in HCV patients as a prototype to monitor immunotherapy of infectious diseases.

In this study, strategies for serum biomarker assessment were developed for therapeutic monitoring of HCV patients. For this purpose, serum chemokine/cytokine levels were measured by cytometric-bead-array in HCV patients, categorized according to immunotherapy response as: non-responder/NR, relapser/REL and sustained-virologic-responder/SVR. The results demonstrated an overall increase of serum chemokine/cytokine levels in HCV patients. In general, therapeutic failure was associated with presence of a predominant baseline proinflammatory pattern with enhanced CCL5/RANTES, IFN-α, IFN-γ along with decreased IL-10 levels in NR and increased IL-6 and TNF in REL. SVR displayed lower baseline proinflammatory status with decreased CXCL8/IL-8, IL-12 and IL-17 levels. The inability to uphold IFN-α levels during immunotherapy was characteristic of NR. Serum chemokine/cytokine signatures further support the deleterious effect of proinflammatory baseline status and the critical role of increased/persistent IFN-α levels to guarantee the sustained virologic response. The prominent baseline proinflammatory milieu observed in NR and REL yielded a restricted biomarker network with small number of neighborhood connections, whereas SVR displayed a network with integrated cytokine connectivity. Noteworthy was that SVR presented a shift towards a proinflammatory pattern upon immunotherapy, assuming a pattern similar to that observed in NR and REL at baseline. Moreover, the immunotherapy guided REL towards a profile similar to SVR at baseline. Analysis of baseline-fold changes during treatment pointed out IFN-α and TNF as high-performance biomarkers to monitor immunotherapy outcome. This knowledge may contribute for novel insights into the treatment and control of the continuous public health threat posed by HCV infection worldwide.

Assessment of Relationship between Wilms' Tumor Gene (WT1) Expression in Peripheral Blood of Acute Leukemia Patients and Serum IL-12 and C3 Levels.

BACKGROUND: Leukemia is a common cancer among children and adolescents. Wilms' tumor gene (WT1) is highly expressed in patients with acute leukemia. It is found as a tumor associated antigen (TAA) in various types of hematopoietic malignancies and can be employed as a useful marker for targeted immunotherapy and monitoring of minimal residual disease (MRD). In this regard, WT1 is a transcription factor that promotes gene activation or repression depending on cellular and promoter context. The purpose of this study was assessment of WT1 gene expression in patients with acute leukemia, measurement of IL-12 and C3 levels in serum and evaluation of the relationship between them. MATERIALS AND METHODS: We evaluated the expression of WT1 mRNA using real-time quantitative RT-PCR and serum levels of IL-12 and C3 using ELISA and nephelometry in peripheral blood of 12 newly diagnosed patients with acute leukemia and 12 controls. RESULTS: The results of our study showed that the average wT1 gene expression in patients was 7.7 times higher than in healthy controls (P <0.05). In addition, IL-12 (P = 0.003) and C3 (P <0.0001) were significantly decreased in the test group compared to controls. CONCLUSIONS: WT1 expression levels are significantly higher in patients compared with control subjects whereas serum levels of interleukin-12 and C3 are significantly lower in patients. Wt1 expression levels in patients are inversely related with serum levels of IL-12 and C3.