Anti-tumor Necrosis Factor Alpha Research Articles

A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis

In clinical studies, the next-generation anti-tumor necrosis factor-alpha (TNF-α) single domain antibody ozoralizumab showed high clinical efficacy shortly after the subcutaneous injection. To elucidate the mechanism underlying the rapid onset of the effects of ozoralizumab, we compared the biodistribution kinetics of ozoralizumab and adalimumab after subcutaneous injection in an animal model of arthritis. Alexa Fluor 680-labeled ozoralizumab and adalimumab were administered by subcutaneous injection once (2 mg/kg) at five weeks after induction of collagen-induced arthritis (CIA) in an animal arthritis model. The time-course of changes in the fluorescence intensities of the two compounds in the paws and serum were evaluated. The paws of the CIA mice were harvested at four and eight hours after the injection for fluorescence microscopy. Biofluorescence imaging revealed better distribution of ozoralizumab to the joint tissues than of adalimumab, as early as at four hours after the injection. Fluorescence microscopy revealed a greater fluorescence intensity of ozoralizumab in the joint tissues than that of adalimumab at eight hours after the injection. Ozoralizumab showed a significantly higher absorption rate constant as compared with adalimumab. These results indicate that ozoralizumab enters the systemic circulation more rapidly and is distributed to the target tissues earlier and at higher levels than conventional IgG antibodies. Our investigation provides new insight into the mechanism underlying the rapid onset of the effects of ozoralizumab in clinical practice.

The inexorable increase of biologic exposure in paediatric inflammatory bowel disease: a Scottish, population-based, longitudinal study.

The use of biologics in paediatric-onset inflammatory bowel disease (PIBD) is rapidly changing. To identify the incidence and prevalence of biologic use within Scottish PIBD services, and to describe patient demographics and outcomes for those patients who required escalation of therapy beyond anti-tumour necrosis factor alpha (anti-TNFα) agents METHODS: We captured a nationwide cohort of prospectively identified patients less than 18 years of age with PIBD (A1 phenotype; diagnosed <17 years of age) within paediatric services over a 4.5-year period (1 January 2015-30 June 2019). All patients who received infliximab, adalimumab, vedolizumab or ustekinumab during the study period and/or received their first dose of these biologics were audited retrospectively. Scotland-wide PIBD-prevalence cases increased from 554 to 644 over the study period. A total of 495 incident new-start biological therapies were commenced on 403 PIBD patients: 295 infliximab (60%), 161 adalimumab (32%), 24 vedolizumab (5%) and 15 ustekunumab (3%). The proportion of new-start biologics changed with infliximab initiation rates decreasing (87%-54%) while adalimumab (13%-31%), vedolizumab (0%-9%) and ustekinumab (0%-6%) all increased. The incidence rate (first dose of new biologic not including biosimilar switch) increased from 6.9% to 8.1% over the study period and point prevalence rates (any biologic use) increased from 20.2% to 43.5% - an average annual percentage increase of 20%. Biosimilar penetration of new-start anti-TNFα agents increased from 3% to 91%. Demographics and outcomes of those patients receiving vedolizumab and ustekinumab were similar. Complete accrual of Scottish nationwide biologic usage within paediatric services demonstrates a rapidly changing, inexorably increasing PIBD biologics landscape.

S983 Baseline Demographics and Disease Characteristics of Patients With Ulcerative Colitis Who Responded to Vedolizumab at Week 6

S983 Baseline Demographics and Disease Characteristics of Patients With Ulcerative Colitis Who Responded to Vedolizumab at Week 6

AVT02: An Adalimumab Biosimilar.

AVT02 (Hukyndra®, Libmyris®) is a biosimilar of the reference anti-tumour necrosis factor alpha monoclonal antibody adalimumab. It is approved for use in all indications for which reference adalimumab is approved. AVT02 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and the pharmacokinetic similarity of the agent has been shown in healthy adult subjects. AVT02 demonstrated clinical efficacy similar to that of reference adalimumab in patients with chronic plaque psoriasis, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of AVT02 were similar to those of reference adalimumab. Switching from reference adalimumab to AVT02 appeared to have no impact on efficacy, safety or immunogenicity. The role of reference adalimumab in the management of immune-mediated inflammatory diseases is well established and AVT02 provides an effective biosimilar alternative for patients requiring adalimumab therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-022-01196-w.

S719 Maternal and Neonatal Outcomes in Vedolizumab and Ustekinumab Exposed Pregnancies: Results From the PIANO Registry

Introduction: Pregnancy outcomes in IBD patients with quiescent disease are similar to the general population. Data from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes (PIANO) registry have demonstrated the safety of anti-tumor necrosis factor alpha (TNFs) and thiopurines in pregnancy. The objective of this study is to provide updated information from the PIANO registry on maternal and fetal outcomes in patients exposed to ustekinumab (UST) and vedolizumab (VDZ). Methods: In this multicenter prospective observational study, we included pregnant women with singleton pregnancies and a diagnosis of inflammatory bowel disease. Questionnaires were administered to women at study intake, each subsequent trimester, delivery, and at 4, 9, and 12 months after birth. Bivariate analyses were utilized to determine the independent effects of specific drug classes on outcomes. The exposure cohorts were VDZ, UST, TNFs, immunomodulators, and combination with biologics and immunomodulators. All were compared to no exposure to biologics/immunomodulators. Results: There were 1642 completed pregnancies with 1581 live births. Maternal mean age was 32.1±4.6 years at delivery with 62 VDZ and 43 UST exposed. Women on UST were more likely to have Crohn’s disease. There was no increased risk of spontaneous abortion, small for gestational age, low birth weight, neonatal intensive care unit stay, congenital malformations, or intrauterine growth restriction with in utero VDZ or UST exposure (Table). The rate of preterm birth was 0% in UST, 12.7% VDZ, 8.2% TNFs, and 9.7% in the unexposed cohort (p = 0.037). Rates of serious and non-serious infections at birth and within the first 12 months of life were comparable among all groups, with an increase in nonserious infections in VDZ group at 4 months, which did not persist at 1 year. There was no increased risk of placental complications in the VDZ cohort compared to the unexposed cohort. UST infant concentrations at birth were increased whereas VDZ concentrations were overall decreased compared to maternal serum drug concentrations. Conclusion: An updated analysis of UST and VDZ exposure during pregnancy suggests no increase in complications compared to TNFs, immunomodulators and combination of biologics with immunomodulators. UST was associated with lower rates of preterm birth and Cesarean section. No signal was found for increased placental events with either therapy. Continuation of UST and VDZ during pregnancy is recommended. Table 1. - Pregnancy Related Complications by Drug Exposure in completed pregnancies Pregnancy Events(% yes) No exposure(n = 430) Anti-TNFs(n = 700) Immuno-modulators(n = 226) Combination: Biologics + Immunomodulators(n = 179) UST(n = 43) VDZ(n = 62) p-value Any pregnancy complication 86/401(21.4%) 123/649(19.0%) 42/208(20.2%) 28/169(16.6%) 10/39(25.6%) 10/59(16.9%) 0.663 SAB (gestation ages ≤140 days) 9/234(3.8%) 18/438(4.1%) 6/136(4.4%) 2/109(1.8%) 2/21(9.5%) 1/30(3.3%) 0.675 SAB (all gestation ages) 11/429(2.6%) 18/697(2.6%) 7/226(3.1%) 2/178(1.1%) 2/43(4.7%) 1/62(1.6%) 0.739 Preterm birth (< 37 weeks) 38/391(9.7%) 53/643(8.2%) 25/204(12.3%) 24/166(14.5%) 0/38(0.0%) 7/55(12.7%) 0.037 Small for gestational age 16/383(4.2%) 31/579(5.4%) 5/202(2.5%) 3/147(2.0%) 1/14(7.1%) 2/35(5.7%) 0.356 LBW (< 2500 g) 21/380(5.5%) 38/635(6.0%) 9/206(4.4%) 8/159(5.0%) 1/38(2.6%) 6/55(10.9%) 0.493 Intrauterine growth restriction 11/429(2.6%) 13/700(1.9%) 1/226(0.4%) 4/179(2.2%) 0/43(0.0%) 1/62(1.6%) 0.455 Cesarean section 154/394(39.1%) 292/650(44.9%) 93/208(44.7%) 90/168(53.6%) 12/38(31.6%) 26/55(47.3%) 0.024 NICU at birth 58/397(14.6%) 107/651(16.4%) 31/209(14.8%) 29/168(17.3%) 4/37(10.8%) 8/55(14.5%) 0.879 Congenital malformations 28/268(10.4%) 61/581(10.5%) 19/150(12.7%) 18/153(11.8%) 7/39(17.9%) 8/59(13.6%) 0.715 Any of the above 275/430(64.0%) 477/700(68.1%) 156/226(69.0%) 128/179(71.5%) 28/43(65.1%) 42/62(67.7%) 0.513 Abruptio Placenta 3/198(1.5%) 5/302(1.7%) 1/93(1.1%) 1/75(1.3%) 0/13(0.0%) 0/31(0.0%) >0.999 Pre-Eclampsia/Eclampsia 18/198(9.1%) 30/302(9.9%) 13/93(14.0%) 7/75(9.3%) 2/13(15.4%) 4/31(12.9%) 0.512 Placenta previa 5/197(2.5%) 9/302(3.0%) 2/93(2.2%) 1/75(1.3%) 0/13(0.0%) 2/31(6.5%) 0.243 Hemorrhage 5/197(2.5%) 5/302(1.7%) 5/93(5.4%) 2/75(2.7%) 3/13(23.1%) 0/31(0.0%) >0.999 Postpartum hemorrhage 6/197(3.1%) 15/302(2.1%) 1/93(1.1%) 5/75(6.7%) 0/13(0.0%) 1/31(3.2%) >0.999 TNF: tumor necrosis factor, UST: ustekinumab, VDZ: vedolizumab, SAB: spontaneous abortion, LBW: low birth weight, g: grams, NICU: neonatal intensive care unit, vs: versus.

Autoinflammatory keratinization diseases

As predisposing factors and pathogenic mechanisms of inflammatory keratinization disorders of the skin have become increasingly elucidated in recent years, a number of inflammatory keratinization disorders are now known to have the excessive activation of innate immunity as their pathogenesis. Autoinflammation-associated pathogeneses have been clarified in patients with generalized pustular psoriasis (GPP), pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Thus, based on these findings, in 2017, we proposed the clinical entity “autoinflammatory keratinization disease (AiKD),” which comprehensively includes inflammatory keratinization disorders with pathogenic mechanisms related to autoinflammation (the excessive activation of innate immunity). In 2017, GPP and associated diseases, PRP type V, and familial KLC came to be considered as AiKDs. In addition to these diseases, hidradenitis suppurative, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome, and AiKDs with hepatitis and autism have been newly recognized as AiKDs. The concept of AiKD may contribute to the selection of novel treatment methods. For example, recognizing hidradenitis suppurativa precisely as an AiKD has resulted in the application of adalimumab, an anti-tumor necrosis factor alpha antibody, as a treatment. The concept of AiKD is thought to be useful toward our accurate understanding of the pathogeneses of inflammatory keratinization disorders and our choice of appropriate treatment methods. As the pathogenic mechanisms of inflammatory keratinization disorders are further elucidated, it is presumed that the number of keratinization diseases whose pathogeneses are associated with autoinflammation will increase and that the number of diseases recognized as AiKDs will grow more and more.

Gastroprotective Effect of Capparis spinosa on Indomethacin-induced Gastric Ulcer in Rats.

Peptic ulcer is an acid-induced lesion that is usually found in the stomach and duodenum. It is usually a case of imbalance between the acid (and other injurious factors) and the mucosal defense mechanisms. Indomethacin is one of the most ulcerogenic drugs that is prescribed over-the-counter for the management of musculoskeletal problems. Capparis spinosa is one of the most important species in the Capparidaceae family, which has a wide range of diversity. Caper (Capparis spinosa L.) is a common member of the genus Capparis (Capparidaceae family). The present study was designed to compare the effect of C. spinosa extract as a gastroprotective agent with indomethacin as an induction agent and ranitidine as a standard drug. To this aim, 40 adult male Wistar rats were randomly divided into 4 groups (n=10 each), including Control +: indomethacin-treated group, Control -: receiving physiological saline solution, C.S: C. spinosa-treated group; and ranitidine-treated group (50 mg/kg) as a standard agent for the treatment of the gastric ulcer. After the experimental period, all the animals were sacrificed by anesthesia overdose and their stomachs were removed. The gastroprotective effect of C. spinosa was investigated by studying prostaglandin E2 (PGE2), Gastrin, anti-tumor necrosis factor alpha (TNF-α), and Interleukin 1 beta (IL1-β), along with histopathological examination. The results showed a significant increase in PGE2 levels in the ranitidine-treated group with a significant reduction in Gastrin, TNF-α, and IL1-β. The recorded data obtained from the histopathological study showed a significant improvement in the treated group with the extract of C. spinosa. The study concluded that C. spinosa had gastroprotective properties possibly through enhancing PGE2 which was acting as anti-inflammatory inhibiting neutrophil infiltration.

The assessment of the cardiovascular risk in rheumatoid arthritis patients on anti TNF therapy

Auto-immune rheumatic diseases are characterised by high levels of inflammation that accelerate the development of atherosclerosis, increasing the cardiovascular risk. Direct evaluation of arteries such as of intima media thickness measurement is a simple test that asesses the cerebral and cardiovascular risk. In the initial stages, an increase of the intimal media thickness can be observed. Later on, atherosclerosis (plaques), stenosis and occlusion of the arteries can be identified. Indirect evaluation of the cardiovascular risk can be performed using serological markers - fibrinogen, C reactive protein, estimated sedimentation rate, total cholesterol, low density lipoproteins and high density lipoproteins, homocysteine levels etc. The presence of certain lifestyle factors that increase the risk, such as smoking, sedentarism and associated pathologies such as obesity, diabetes, hypertension were assesed in patients with rheumatoid arthritis. The aim of the study is to prove the relationship between anti-tumor necrosis factor alpha therapy effect on the cardiovascular risk in rheumatoid arthritis patients

Identified potential biomarkers may predict primary nonresponse to infliximab in patients with ulcerative colitis

Primary nonresponse to infliximab in patients with ulcerative colitis (UC) is common. However, there are currently no effective biomarkers for this prediction. This study aimed to identify potential predictors for precision anti-tumor necrosis factor-alpha treatment in patients with UC. Four GPL570 datasets (GSE14580, GSE12251, GSE23597, and GSE16879) were included in this study. Sixty-nine differentially expressed genes (DEGs) were identified, while 67 were up-regulated and two were down-regulated by comparing the gene expression in response samples with the nonresponse samples. Gene Ontology analysis showed that DEGs were mostly enriched in neutrophil-mediated immunity, neutrophil activation, neutrophil activation involved in the immune response, neutrophil degranulation, and leukocyte migration. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that these DEGs were mostly enriched in cytokine-cytokine receptor interactions and interleukin (IL)-17 signalling pathways. After protein-protein interaction network analysis, verification by test set, and confirmation of clinical UC samples, S100 calcium-binding protein A8 (S100A8), S100A9, triggering receptor expressed on myeloid cells 1 (TREM1), toll-like receptor 2 (TLR2), IL1B, and formyl peptide receptor 1 (FPR1) were identified as the hub genes. We found that the immune cell composition in the intestinal tissues of UC patients with primary nonresponse included naïve CD4+ T cells, memory resting CD4+ T cells, resting natural killer cells, resting dendritic cells, activating dendritic cells, eosinophils, and neutrophils. Among these, neutrophils showed the most significant differences. In addition, all six potential predictors were significantly associated with the neutrophil count. Our study identified six potential biomarkers, namely S100A8, S100A9, TREM1, TLR2, IL1B, and FPR1, and one type of immune cell, neutrophils, between UC patients with response and primary nonresponse to infliximab. We speculated that changes in the expression of these six potential biomarkers combined with changes in the activity or local quantity of neutrophils might help predict primary nonresponse to infliximab in patients with UC.

Anti-tumor necrosis factor-alpha treatment in pediatric patients with pars planitis: a single-center experience from Turkey.

To evaluate the effectiveness and safety of anti-tumor necrosis factor-alpha (anti-TNF-alpha) treatment (Adalimumab [ADA]) combined with immunomodulatory agents (IMAs) in the treatment of pars planitis (PP). The patients with PP who were treated with anti-TNF-alpha agents for at least six months were qualified for the chart review. The outcome parameters were the steroid-free remission state, the best-corrected visual acuity (BCVA) and the central macular thickness (CMT) of the patients at the last visit. After a mean total follow-up time of 15.5 ± 5.8months (8-24months), all the cases were in steroid-free remission at the last visit. The mean BCVA increased, and the mean CMT decreased significantly at the last visit (p < 0.001, p < 0.001, respectively). ADA combined with IMAs offers effective and safe treatment modalities in the control of chronic intraocular inflammation in PP cases.

Tumor Necrosis Factor-Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is an autoimmune disease that, if untreated or poorly controlled, can cause significant morbidity in terms of loss of physical function and higher mortality due to higher cardiovascular risk. The standard of care for this disease is the use of disease-modifying antirheumatic drugs (DMARDs). However, patients unable to reach low disease activity or remission and patients unable to tolerate conventional DMARDs will be switched to biologic therapy, a subset of which includes anti-tumor necrosis factor-alpha inhibitors. Since tumor necrosis factor-alpha inhibitors (TNFi) inhibit the inflammatory cascade, they also play an essential role in dampening the progression of atherosclerosis and altering the risk of cardiovascular outcomes in RA.In this study, we assessed the risk of cardiovascular diseases, namely, congestive heart failure, nonfatal myocardial infarction, cerebrovascular disease, and coronary artery disease. We carried out the analysis by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and conducted a literature search utilizing the following databases: PubMed, Science Direct, and Cochrane Library. Using the search strategy, we found a total of 19 articles that fit the inclusion and exclusion criteria, in addition to passing the risk of bias assessment. This is composed of three systematic reviews with meta-analyses, three randomized control studies, four narrative reviews, and nine cohort studies. In this systematic review, it was found that treatment with TNFi causes a corresponding reduction in the risk of cardiovascular events. This review encourages further dissection into the inner workings of TNFi in reducing the risk of cardiovascular disease among patients with RA.

Efficacy of adalimumab in pediatric generalized pustular psoriasis: case series and literature review

Background Generalized pustular psoriasis (GPP) is a rare, severe, and sometimes fatal form of childhood psoriasis. The first line therapies include acitretin, cyclosporin A, and methotrexate which take effect slowly and have varying long-term side effects for children. Recently, the anti-tumor necrosis factor-alpha (TNF-α), adalimumab has shown efficacy in adult patients with pustular psoriasis; however, there is lack of evidence of its usage in the pediatric population. Methods Data on efficacy of adalimumab in treating pediatric GPP along with a literature review are presented. Results A total of seven patients had marked clearance and reduction in PGA and systemic/laboratory score within the first week of first injection and achieved almost complete clearance of skin lesions by 1-month follow up. In literature, adalimumab treating pustular psoriasis in pediatric has been described in six children who failed in prior treatment. All six patients showed a satisfactory therapeutic effect. Conclusions Subcutaneous injection of adalimumab every other week in the treatment of children with GPP has significant clinical efficacy with rapid clearance of skin lesions, providing a novel alternative for children with pustular psoriasis who responded poorly to traditional treatment or are not suitable for traditional treatment.

Efficacy of Calcineurin Inhibitors for Induction of Remission in Intestinal Behçet's Disease.

The efficacy of calcineurin inhibitors (CNIs) for induction of remission in intestinal Behçet's disease (intestinal BD) has not been explored. A multicenter retrospective case series study of patients with active intestinal BD treated with CNIs (cyclosporin and tacrolimus) was conducted. Of 16 patients, 12 (75%) showed a clinical response and 5 (31.3%) achieved clinical remission after 2 weeks of CNI treatment. Similar efficacy of CNIs was observed even in 7 patients refractory to antitumor necrosis factor-alpha therapies. Endoscopic improvement was observed in 11 of 12 patients. CNIs may be promising treatment options for refractory intestinal BD.

Superior Effectiveness of Tofacitinib Compared to Vedolizumab in Anti-TNF-experienced Ulcerative Colitis Patients: A Nationwide Dutch Registry Study

Clinicians face difficulty in when and in what order to position biologics and Janus kinase inhibitors in patients with anti-tumor necrosis factor-alpha (TNF) refractory ulcerative colitis (UC). We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF-exposed patients with UC in our prospective nationwide Initiative on Crohn and Colitis Registry. Patients with UC who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment were identified in the Initiative on Crohn and Colitis Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (Simple Clinical Colitis Activity Index ≤2), biochemical remission (C-reactive protein ≤5 mg/L or fecal calprotectin ≤250 μg/g), and safety outcomes were compared after 52 weeks of treatment. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias. Overall, 83 vedolizumab- and 65 tofacitinib-treated patients were included. Propensity score-weighted analysis showed that tofacitinib-treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at weeks 12, 24, and 52 compared with vedolizumab-treated patients (odds ratio [OR], 6.33; 95% confidence interval [CI], 3.81-10.50; P < .01; OR, 3.02; 95% CI, 1.89-4.84; P < .01; and OR, 1.86; 95% CI, 1.15-2.99; P= .01; and OR, 3.27; 95% CI, 1.96-5.45; P < .01; OR, 1.87; 95% CI, 1.14-3.07; P= .01; and OR, 1.81; 95% CI, 1.06-3.09; P= .03, respectively). There was no difference in infection rate or severe adverse events. Tofacitinib was associated with superior effectiveness outcomes compared with vedolizumab in anti-TNF-experienced patients with UC along with comparable safety outcomes.

Serum Tumor Necrosis Factor-Alpha Levels in Acute Leukemia and Its Prognostic Significance.

IntroductionTumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that facilitates malignant cells in immune evasion, survival, and treatment resistance by generating a favorable milieu for them. It is shown to be ectopically produced by malignant/leukemic and immune cells in the tumor microenvironment, providing a tumor-supportive environment and playing an important part in the establishment and progression of malignant cells. It is linked to hyperleukocytosis, high blast count, and poor clinical outcomes in acute leukemia (AL). Considering the varied role and different expression patterns of tumor necrosis factor-alpha in acute leukemia and its clinical relevance, the present study was planned to monitor the level of tumor necrosis factor-alpha in patients with acute leukemia and its correlation with disease outcome. The aim of this study was to monitor the level of tumor necrosis factor-alpha in patients with acute leukemia at the time of diagnosis and after induction chemotherapy.Material and methodsThe study included cases classified as acute leukemia based on morphological examination, bone marrow analysis, and flow cytometry. In all patients with acute leukemia (n = 90) and controls (n = 10), the serum tumor necrosis factor-alpha level was measured using a Diaclone Human ELISA kit (Diaclone, Besancon, France) (solid phase sandwich ELISA) at diagnosis and after induction chemotherapy.ResultsTumor necrosis factor-alpha levels were substantially higher in T-acute lymphoblastic leukemia (T-ALL) cases, followed by acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL), at the time of diagnosis, compared to the control. A significant reduction in serum tumor necrosis factor-alpha level was seen in patients with acute leukemia after induction phase chemotherapy (P < 0.05). Tumor necrosis factor-alpha levels were considerably reduced (P < 0.001) in the majority of acute leukemia cases after the induction phase, while high tumor necrosis factor-alpha levels were positively correlated with incomplete remission status in the remaining cases.ConclusionTumor necrosis factor-alpha is involved in the progression of acute leukemia and its relapse. High levels of tumor necrosis factor-alpha are linked to leukocytosis, high blast counts, and worse survival in patients with acute leukemia. Monitoring of tumor necrosis factor-alpha may be helpful in patients with acute leukemia in view of available antitumor necrosis factor-alpha therapy.

De-Escalation of Anti-Tumor Necrosis Factor Alpha Agents and Reduction in Adverse Effects: A Systematic Review.

Background: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle–Ottawa scale (non-RCTs). Results: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis. Conclusion: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question. Registration: PROSPERO CRD42021252977.

The gut fungal and bacterial microbiota in pediatric patients with inflammatory bowel disease introduced to treatment with anti-tumor necrosis factor-\u03b1

Pediatric inflammatory bowel disease (PIBD) is a globally increasing chronic inflammatory disease associated with an imbalanced intestinal microbiota and treated with several treatment options, including anti-tumor necrosis factor alpha (TNF-α), such as infliximab (IFX). Up to half of the patients do not respond to the drug and there are no methods for response prediction. Our aim was to predict IFX response from the gut microbiota composition since this is largely unexplored in PIBD. The gut microbiota of 30 PIBD patients receiving IFX was studied by MiSeq sequencing targeting 16S and ITS region from fecal samples collected before IFX and two and six weeks after the start of treatment. The response to IFX induction was determined by fecal calprotectin value < 100 µg/g at week six. The bacterial microbiota differed significantly between response groups, with higher relative abundance of butyrate-producing bacteria in responders compared to non-responders at baseline, validated by high predictive power (area under curve = 0.892) for baseline Ruminococcus and calprotectin. Additionally, non-responders had higher abundance of Candida, while responders had higher abundance of Saccharomyces at the end of the study. The gut microbiota composition in PIBD patients could predict response to IFX treatment in the future.

The impact of gender and sex in psoriasis: What to be aware of when treating women with psoriasis.

Background:Psoriasis is a common chronic inflammatory skin disease with an exceptionally high burden for women.Objective:Sex-dependent differences in disease manifestation, severity, treatment choices, subjective disease perception, and the impact on quality of life and risk factors are described and comprehensively discussed.Methods:A literature search was conducted using MEDLINE (PubMed) and the Cochrane Library for systematic reviews to investigate the challenges in treating women with psoriasis.Results and conclusions:The incidence, prevalence, and manifestation of psoriasis of the skin are similar between different sexes. Genetic and environmental factors such as obesity and metabolic syndrome are risk factors and are not equally relevant or pronounced in women and men. Overall, women have a lower disease severity measured by the Psoriasis Area Severity Index, which is associated with a higher impairment of their life quality measured by the Dermatology Life Quality Index compared with men. In addition, women with psoriasis are more likely to have depression than men. Hormonal factors affect psoriasis, with a correlation of high estrogen levels and improvement of psoriasis. Data regarding differences in prescribing patterns of systemic treatments and the severity of psoriasis are not entirely consistent. Registry studies show that men tend to have more severe psoriasis and, in some cases, are prescribed systemic therapies more frequently. Women tend to respond better to systemic treatments and to experience more adverse events. Treatment options are the same for both sexes, except during pregnancy and lactation. Various treatment options are contraindicated due to fear of fetal or neonate harm and lack of data. Topical steroids can be prescribed with a high degree of safety during pregnancy. For other topical therapies (calcineurin inhibitors and vitamin D analogs), no studies of adverse effects in pregnancy are available, and safety data mainly stem from studies examining effects after systemic administration. Antitumor necrosis factor monoclonal antibodies (except for certolizumab pegol) have been associated with a possible increased risk of preterm birth, low gestational age, and cesarean deliveries. Prospective data on the safety of biologics other than antitumor necrosis factor-alpha antibodies to accurately assess whether novel biologics (eg, anti-interleukin 17, 12/23, 23) can be used for systemic therapy in pregnancy are lacking or currently being conducted.

Facial demodicosis in the immunosuppressed state: a retrospective case series from a tertiary referral center.

Data on Demodex in the immunosuppressed state is limited, focusing mainly on patients with human immunodeficiency virus and hematological malignancies. The aim of this study was to describe the manifestations of facial demodicosis in diverse immunosuppressive states. The medical records of all patients followed at a Demodex outpatient clinic of a tertiary medical center from January 2008 to November 2020 were retrospectively reviewed. Data on patients who were immunosuppressed while with demodicosis were retrieved. The cohort included 28 patients (17 women and 11 men; median age, 58 years). Types of immunosuppression included treatments with hydroxyurea for polycythemia vera/essential thrombocytosis, mycophenolic acid, tacrolimus, and prednisone for liver and/or kidney transplantation, prednisone with cyclosporine/methotrexate/azathioprine/rituximab mainly for autoimmune diseases, mercaptopurine with/without anti-tumor necrosis factor alpha (TNF-α) for Crohn's disease, chemotherapy for neoplasms, anti-TNF-α for psoriasis, and Cushing's syndrome. The clinical types of demodicosis included: papulopustular, erythematotelangiectatic and fulminant rosacea, hyperpigmented, pityriasis folliculorum, pustular folliculitis, and dermatitis. The diverse clinical presentations led to various differential diagnoses. Topical treatment with ivermectin (monotherapy/combination with other treatments) was effective. Clinicians treating immunosuppressed patients should be familiar with the different forms of demodicosis and include them in the differential diagnosis of facial eruptions.

The Effects of Freshwater Clam (Corbicula fluminea) Extract on Serum Tumor Necrosis Factor-Alpha (TNF-α) in Prediabetic Patients in Taiwan.

Freshwater clam extract (FCE) is a functional food that regulates the immune system and has been demonstrated in numerous studies to display desirable anti–tumor necrosis factor-alpha (TNF-α) responses. In addition, excess TNF-α production is positively associated with type 2 diabetes. However, few longitudinal clinical studies evaluating the efficiency and toxicity of FCE are available. This article reports that patients with prediabetes who received FCE had a desirable outcome of a reduction in serum TNF-α for a long period. This was a double-blind, randomized, parallel clinical trial conducted using FCE intervention and placebo groups, and 36 patients with prediabetes were enrolled. Two grams of FCE or placebo was consumed daily for 180 consecutive days. The serum of the participants was collected at four time points (0M: before the intervention; 3M: after 3 months of intervention; 6M: after 6 months of intervention; 12M: 6 months after cessation of intervention at 6M). A serum TNF-α concentration higher than 4.05 pg/mL was defined as a cut-off value. FCE reduced serum TNF-α in all participants at 6M and 12M. Moreover, FCE significantly suppressed serum TNF-α concentrations at 6M and 12M and inhibited TNF-α release with time series in subjects with elevated TNF-α values. FCE intervention effectively reduced serum TNF-α and persistently sustained the effects for half a year in patients with prediabetes. Gas chromatography–mass spectrometry (GS-MS) analysis revealed that the major components of FCE were phytosterols and fatty acids, which exerted anti-inflammatory and anti-TNF-α abilities. Hence, FCE has the potential to be developed as a natural treatment for prediabetic patients in Taiwan.