TNF-α Inhibitors Research Articles

Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation

Inflammatory bowel diseases (IBDs), such as Crohn's disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-α) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-α Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-α (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-α Ab neutralized TNF-α inhibition in vitro. The effects of anti TNF-α Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.

EFFICACY AND SAFETY OF VEDOLIZUMAB AND TUMOR NECROSIS FACTOR INHIBITORS IN THE TREATMENT OF STEROID-REFRACTORY MICROSCOPIC COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Tumor necrosis factor (TNF-α) inhibitors and the α4β7 integrin antagonist, vedolizumab have been investigated as a treatment option for patients with steroid-refractory microscopic colitis (MC) with controversial findings.

Inhibition of the type 1 diabetes candidate gene PTPN2 aggravates TNF-α-induced human beta cell dysfunction and death.

TNF-α plays a role in pancreatic beta cell loss in type 1 diabetes mellitus. In clinical interventions, TNF-α inhibition preserves C-peptide levels in early type 1 diabetes. In this study we evaluated the crosstalk of TNF-α, as compared with type I IFNs, with the type 1 diabetes candidate gene PTPN2 (encoding protein tyrosine phosphatase non-receptor type 2 [PTPN2]) in human beta cells. EndoC-βH1 cells, dispersed human pancreatic islets or induced pluripotent stem cell (iPSC)-derived islet-like cells were transfected with siRNAs targeting various genes (siCTRL, siPTPN2, siJNK1, siJNK3 or siBIM). Cells were treated for 48 h with IFN-α (2000 U/ml) or TNF-α (1000 U/ml). Cell death was evaluated using Hoechst 33342 and propidium iodide staining. mRNA levels were assessed by quantitative reverse transcription PCR (qRT-PCR) and protein expression by immunoblot. PTPN2 silencing sensitised beta cells to cytotoxicity induced by IFN-α and/or TNF-α by 20-50%, depending on the human cell model utilised; there was no potentiation between the cytokines. We silenced c-Jun N-terminal kinase (JNK)1 or Bcl-2-like protein 2 (BIM), and this abolished the proapoptotic effects of IFN-α, TNF-α or the combination of both after PTPN2 inhibition. We further observed that PTPN2 silencing increased TNF-α-induced JNK1 and BIM phosphorylation and that JNK3 is necessary for beta cell resistance to IFN-α cytotoxicity. We show that the type 1 diabetes candidate gene PTPN2 is a key regulator of the deleterious effects of TNF-α in human beta cells. It is conceivable that people with type 1 diabetes carrying risk-associated PTPN2 polymorphisms may particularly benefit from therapies inhibiting TNF-α.

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies

In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.

Anti-inflammatory potential of selective small compounds by targeting TNF-α & NF-kB signaling: a comprehensive molecular docking and simulation study

Tumor necrosis factor alpha (TNF-α) is the major cause of inflammation in autoimmune diseases like rheumatoid arthritis (RA). It’s mechanisms of signal transduction through nuclear factor kappa B (NF-kB) pathway via small molecules such as metabolite crosstalk are still elusive. In this study, we have targeted TNF-α and NF-kB through metabolites of RA, to inhibit TNF-α activity and deter NF-kB signaling pathways, thereby mitigating the disease severity of RA. TNF-α and NF-kB structure was obtained from PDB database and metabolites of RA were selected from literature survey. In-silico studies were carried out by molecular docking using AutoDock Vina software and further, known TNF-α and NF-kB inhibitors were compared and revealed metabolite’s capacity to targets the respective proteins. Most suitable metabolite was then validated by MD simulation to verify its efficiency against TNF-α. Total 56 known differential metabolites of RA were docked with TNF-α and NF-kB compared to their corresponding inhibitor compounds. Four metabolites such as Chenodeoxycholic acid, 2-Hydroxyestrone, 2-Hydroxyestradiol (2-OHE2), and 16-Hydroxyestradiol were identified as a common TNF-α inhibitor’s having binding energies ranging from −8.3 to −8.6 kcal/mol, followed by docking with NF-kB. Further, 2-OHE2 was selected because of having binding energy −8.5 kcal/mol, found to inhibit inflammation and the effectiveness was validated by root mean square fluctuation, radius of gyration and molecular mechanics with generalized born and surface area solvation against TNF-α. Thus 2-OHE2, an estrogen metabolite was identified as the potential inhibitor, attenuated inflammatory activation and can be utilized as a therapeutic target to disseminate severity of RA.

Cytokine Signatures in Psoriatic Arthritis Patients Indicate Different Phenotypic Traits Comparing Responders and Non-Responders of IL-17A and TNFα Inhibitors.

This study aimed to explore the dynamic interactions between 32 cytokines and biomarkers in Psoriatic Arthritis (PsA) patients to compare cytokine signatures of treatment responders and non-responders. Biomarkers were measured before and after four months of treatment in 39 PsA patients initiating either Tumor Necrosis Factor alpha inhibitor (TNFi) or Interleukin-17A inhibitor (IL-17Ai). Response to treatment was defined by the composite measure, Disease Activity in Psoriatic Arthritis (DAPSA). A two-component principal component analysis (PCA) was implemented to describe cytokine signatures comparing DAPSA50 responders and non-responders. The cytokine signature of TNFi responders was driven by the correlated cytokines interferon γ (IFNγ) and IL-6, additionally associated with IL-12/IL-23p40, TNFα, and CRP, while the cytokine signature of TNFi non-responders was driven by the correlated cytokines IL-15, IL-8, and IFNγ. IL-17Ai responders were characterized by contributions of strongly correlated Th17 inflammatory cytokines, IL-17A, IL-12/IL-23p40, IL-22 to the cytokine signature, whereas IL-17A and IL-12/IL-23p40 did not demonstrate significant contribution in IL-17Ai non-responders. Based on PCA results it was possible to differentiate DAPSA50 responders and non-responders to treatment, endorsing additional examination of cytokine interaction models in PsA patients and supporting further PsA patient immune stratification to improve individualized treatment of PsA patients.

Psoriasis in children and adolescents : Short update and guideline-based treatment

Psoriasis is nowadays regarded as amultifactorial, inflammatory, immune-mediated systemic condition with predominant involvement of the skin. It starts in about one third of cases in childhood and adolescence and is often accompanied by marked impairment of the quality of life of sufferers and their parents. Aside from genetic disposition, trigger factors such as streptococcal infections are notably involved in manifestation and in exacerbations. The harmful role of comorbidities even in the young, particularly of obesity, has been well documented. Treatment options have considerably improved following the approval of five biologic agents in childhood but are still insufficiently used. The present article gives ashort overview of current knowledge and the recommendations of the updated German guideline. Besides frequent types, unusual presentations such as pustular psoriasis, psoriasis dermatitis, and paradoxical psoriasis induced by tumor necrosis factor alpha (TNF-α) inhibitors are addressed.

Blood Cell Biomarkers of Inflammation and Cytokine Levels as Predictors of Response to Biologics in Patients with Psoriasis.

For people with psoriasis, biomarkers aiding in the personalization of treatment with biologics are needed. We examined the usefulness of several biomarkers of inflammation in this respect. The neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) were measured in patients with psoriasis initiating TNF-α inhibitors (n = 131), IL-17/IL-17R inhibitors (n = 65), or IL-23/IL-12/23 inhibitors (n = 50). The blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, IL-17A, IL-6, soluble IL-6 receptor (sIL-6R), and soluble IL-6 signal transducer (sIL-6ST) were measured in patients initiating adalimumab (n = 62) or IL-17/IL-17R inhibitors (n = 24). Treatment response was defined by a psoriasis area and severity index (PASI) ≤ 2 three months after treatment initiation. Responders to TNF-α inhibitors had a lower NLR at baseline than non-responders (median and interquartile range (IQR) 2.15 (1.67-2.86) vs. 2.54 (1.88-3.55); p = 0.04). Responders to treatment with adalimumab had lower IL-6 levels at baseline than non-responders (0.99 (0.42-1.4) vs. 1.62 (0.96-2.41) pg/mL; p = 0.02). For the majority of patients, the IL-17A, IL-1β, and IFN-γ levels were below quantification limits. NLR and IL-6 may serve as predictive biomarkers of treatment response to TNF-α inhibitor therapy in patients with psoriasis.

After an initial balance favoring collagen formation and mineralization, bone turnover markers return to pre-treatment levels during long-term TNF-α inhibition in patients with ankylosing spondylitis.

Bone turnover balance favors bone formation, especially mineralization, during the first 3 years of treatment with TNF-α inhibitors (TNFi). Our aim was to evaluate the course of serum bone turnover markers (BTM) and to investigate if facilitation of mineralization reflected by BTM BALP continues to increase during 6 years of TNFi treatment in patients with ankylosing spondylitis (AS) in daily clinical practice. Included were outpatients from the University Medical Center Groningen (UMCG) participating in the Groningen Leeuwarden Axial SpA (GLAS) cohort who were treated with TNFi for at least 6 years. Serum markers of collagen resorption, bone regulation, collagen formation and facilitator of bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured at baseline, 3 and 6 months, 1, 2, 4 and 6 years. Z-scores were calculated to correct for age and gender. 53 AS patients were eligible for analyses (66% male, mean age 39±11 years). Disease activity showed rapid and sustained improvement after start of TNFi. Evaluating BTM, sCTX did not significantly change during 6 years of treatment. OC was only significantly increased at 3 months compared to baseline, with median change in Z-score of +0.5. PINP significantly increased at 3 and 6 months and 2 years of treatment, with maximum median change in Z-score of +0.3. Interestingly, BALP was significantly increased at all time points up to and including 2 years of TNFi treatment, with maximum change in median Z-score of +1.2, and decreased thereafter. In AS patients receiving long-term TNFi, bone turnover balance favored collagen formation and facilitation of mineralization during the first 2 years of treatment. Thereafter, at 4 and 6 years of follow-up, BTM Z-scores returned to pre-treatment levels.

Ferroptosis: a new target for iron overload-induced hemophilic arthropathy synovitis.

Iron deposition is closely related to developing haemophilic arthropathy (HA). Studying the relationship between ferroptosis signal expression and iron overload in HA synovium facilitates understanding the pathogenesis of joint synovial hyperplasia in bloodborne arthritis and the development of new protective methods. The knee synovium was collected from HA and osteoarthritis (OA) patients, and pathological changes were analysed by HE and Prussian blue staining. Ferroptosis phenotypes were examined by immunohistochemistry and western blotting. Moreover, ferric ammonium citrate (FAC)-induced was used to construct an in vitro iron overload model to investigate the relationship between iron overload and ferroptosis in synovial fibroblasts (FLS). Furthermore, the factors influencing ferroptosis in FLS were explored. Iron deposition, cell proliferation, and vascular proliferation in the synovium of HA were more obvious. Ferroptosis in HA synovium appears to inhibit. FLS ferroptosis increased with iron accumulation, malondialdehyde (MDA) in cells, and glutathione (GSH) depletion. TNF-α plays a protective role in this process. Blocking the action of TNF-α and inducing ferroptosis significantly reduced synovial proliferation. TNF-α inhibitors combined with a ferroptosis inducer may be a new therapeutic method for HA synovitis.

The Role of TNF-α in Rheumatoid Arthritis

Rheumatoid arthritis (RA) induces articular damage through autoimmunity. Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis of RA. TNF-α binds to its receptors to recruit certain molecules and forms two kinds of complexes (complex Ⅰ and Ⅱ) to regulate the pro-survival, apoptosis, and necrosis of cells. TNF-α upregulates RA by the methylation and acetylation of the RA synovial fibroblast gene and causes RA-derived joint damage through the induction of osteoclasts. Two TNF-α receptors mediate RA in opposite directions. TNF-α has been a target for the treatment of RA in which TNF-α inhibitors (TNFi) are administrated periodically for RA patients. Several mechanisms in the RA-related TNF-α signaling pathways remain imprecise including the regulation of regulatory T cells, osteoclast induction, and the potential interaction with the hypoxia-inducible factor. Further investigation into these questions may point out new methods for RA treatment to overcome the defects of current TNFi such as the anti-drug antibodies.

Clinical and Demographic Features and Treatment Approaches for Inflammatory Bowel Diseases (Crohn’s Disease, Ulcerative Colitis) in the Russia. The Primery Results of the Analysis of the National Register

The National Registry of Patients with Inflammatory Bowel Disease (IBD) in the Russian Federation was established to study the epidemiological and clinical characteristics of patients and evaluate the actual clinical practice of medical and surgical treatment.AIM: to analyze the data of patients with IBD in the Russian Federation including clinical and demographic characteristics, medical status of patients, the frequency of use of various classes of drugs and response to treatment, the survival rates of advanced therapy drugs and the reasons for their cancellation.METHODS: from May 2017 to August 2021, depersonalized data of 3827 adult patients with IBD (ulcerative colitis (UC) – 2358 pts, Crohn's disease (CD) - 1469 pts) from 80 regions of the Russian Federation were included in the registry, both with previously and newly diagnosed UCor CD, who are in inpatient or outpatient care.RESULTS: in our population, the ratio of UC: CD was 1.6:1. The distribution of patients by sex was the same. The average age of patients in the registry was 40.6±13.1 (13-83 years) for UC and 38.5±14.3 (15-75 years) for CD, the half of patients were in the age range of 21-40 years for both diseases. The average age of disease onset did not differ for UC and CD and was 35.3 year (12-75 years) and 31.2 year (14-72 years) respectively. The duration between the onset of symptoms and the establishment of a diagnosis was 13.2 months in UC, and statistically significantly longer in CD - 34.8 months (P<0.01). The proportion of smokers in CD patients was statistically significantly higher than in UC ones (14.6% versus 9.6%, respectively, P<0.001). The incidence of disability was also significantly higher in CD than in UC patients (41.7% vs. 29.8%, P<0.01). The diagnosis of mild UC was established in 36% of cases, moderate UC occurred in 48.9% of patients, severe UC in 14.2% of patients. For the first time, the frequency of acute severe UC (1%) was estimated. The majority of patients had total UC (56.8%), 33% had left-side colitis, and 9.4% had proctitis. CD was divided by localization into ileocolitis 55.9%, terminal ileitis 23.9%, colitis 20.2%, perianal lesions were noted in 32.5% of cases. The overall complication rate in CD was 46% (681 patients), of which the most common were strictures - 48% and fistulas- 25.1%.Frequencyof extra intestinal manifestations did not differ in UC and CD patients and was 20.1% (473 patients) and 24.5% (360 patients), respectively. Of these, musculoskeletal lesions were more common (41.6% in UC, 42% in CD), lesions of the skin, eyes, mucous membranes, liver, anemia were also noted. In the treatment of IBD, steroids were used most often (79.3% and 65% in UC and CD, respectively), followed by 5-ASA - 47% in UC, 32.4% in CD. Immunosuppressant’s in CD were prescribed significantly more often (28.4%) than in UC (11%) (p<0.05). Biologics were used in 20.6% of UC patients and in 30% of CD patients. The highest 2-year survival of advanced therapy was noted for ustekinumab in CD (96%), for tofacitinib in UC (89.3%), and for vedolizumab in both UC and CD (92.5% and 88.4% respectively). The survival rates of all TNF-α inhibitors were approximately the same and varied within 58.1-72.4% in UC and 60-70% in CD. The most common reasons for discontinuation of advanced treatment were lack of efficacy/loss of response in both UC and CD. The second common reason was achieving remission. Certolizumab pegol in CD was canceled for this reason most often- 22.7% of cases. A small number of patients discontinued treatment due to adverse events: for UC - 1 patient each on adalimumab, golimumab, and tofacitinib, and 7 patients on infliximab, for CD- 5 patients on infliximab and adalimumab (9.6% and 7.5%, respectively) and 2 patients (4.6%) on certolizumab. Unfortunately, the proportion of discontinuation for non-medical reasons was significant and varied from 7% to 50% for different drugs. In some patients, the reason for discontinuation of therapy remained unknown.CONCLUSION: The difficulties of differential, often untimely diagnosis of CD and UC, the predominance of complicated and severe forms against the background of an increase in morbidity and prevalence, and at the same time the lack of adequate statistical accounting of CD and UC, make it necessary to create a unified clinical register of patients with IBD. The register of IBD patients will provide a holistic picture of the IBD situation in the country, including optimizing the use of budget funds for the treatment of patients with CD and UC, ensuring their rational planning.

COVID-19 vaccination in psoriasis patients receiving systemic treatment: A prospective single-center study.

The rate of seroconversion after COVID-19 vaccination in patients with moderate to severe psoriasis requiring systemic treatment is poorly understood. The aim of this prospective single-center cohort study performed between May 2020 and October 2021 was to determine the rate of seroconversion after COVID-19 vaccination in patients under active systemic treatment for moderate to severe psoriasis. Inclusion criteria were systemic treatment for moderate to severe psoriasis, known COVID-19 vaccination status, and repetitive anti-SARS-CoV-2-S IgG serum quantification. The primary outcome was the rate of anti-SARS-CoV-2-S IgG seroconversion after complete COVID-19 vaccination. 77 patients with a median age of 55.9 years undergoing systemic treatment for moderate to severe psoriasis were included. The majority of patients received interleukin- (n=50, 64.9%) or tumor necrosis factor (TNF)-α inhibitors (n=16, 20.8%) as systemic treatment for psoriasis; nine patients (11.7%) were treated with methotrexate (MTX) monotherapy, and one patient each received dimethyl fumarate (1.3%), respectively apremilast (1.3%). All included patients completed COVID-19 vaccination with two doses over the course of the study. Serum testing revealed that 74 patients (96.1%) showed an anti-SARS-CoV-2-S IgG seroconversion. While all patients on IL-17A, -12 or -12/23 inhibitors (n=50) achieved seroconversion, three of 16 patients (18.8%) receiving MTX and/or a TNF-α inhibitor as main anti-psoriatic treatment did not. At follow-up, none of the patients had developed symptomatic COVID-19 or died from COVID-19. Anti-SARS-CoV-2-S IgG seroconversion rates following COVID-19 vaccination in psoriasis patients under systemic treatment were high. An impaired serological response, however, was observed in patients receiving MTX and/or TNF-α inhibitors, in particular infliximab.

Anti-Inflammatory and Gut Microbiota Modulating Effects of Probiotic Lactobacillus paracasei MSMC39-1 on Dextran Sulfate Sodium-Induced Colitis in Rats

Probiotics have been shown to possess several properties, depending on the strain. Some probiotics have important roles in preventing infection and balancing the immune system due to the interaction between the intestinal mucosa and cells in the immune system. This study aimed to examine the properties of three probiotic strains using the tumor necrosis factor-alpha (TNF-α) inhibition test in colorectal adenocarcinoma cells (Caco-2 cells). It was revealed that the viable cells and heat-killed cells of the probiotic L. paracasei strain MSMC39-1 dramatically suppressed TNF-α secretion in Caco-2 cells. The strongest strains were then chosen to treat rats with colitis induced by dextran sulfate sodium (DSS). Viable cells of the probiotic L. paracasei strain MSMC39-1 reduced aspartate transaminase and alanine transaminase in the serum and significantly inhibited TNF-α secretion in the colon and liver tissues. Treatment with the probiotic L. paracasei strain MSMC39-1 alleviated the colon and liver histopathology in DSS-induced colitis rats. Furthermore, supplementation with probiotic L. paracasei strain MSMC39-1 increased the genus Lactobacillus and boosted the other beneficial bacteria in the gut. Thus, the probiotic L. paracasei strain MSMC39-1 exhibited an anti-inflammation effect in the colon and modulated the gut microbiota.

COVID-19 Vaccine Booster Shot Preserves T Cells Immune Response Based on Interferon-Gamma Release Assay in Inflammatory Bowel Disease (IBD) Patients on Anti-TNFα Treatment.

Immune-modifying treatment in inflammatory bowel disease (IBD) impairs the humoral response. The role of T lymphocytes in this setting is still unclear. This study aims to assess if a booster shot (third dose) of BNT162b2 mRNA COVID-19 vaccine enhanced the humoral response and elicited cellular immunity in IBD patients on different immuno-therapy regimens compared to healthy controls (HCs). Five months after a booster dose, serological and T-cell responses were assessed. The measurements were described using geometric means with 95% confidence intervals. The differences between study groups were assessed by Mann-Whitney tests. Seventy-seven subjects (n = 53 IBD patients and n = 24 HCs), who were fully vaccinated and not previously SARS-CoV-2 infected, were recruited. Regarding the IBD patients, 19 were affected by Crohn's disease and 34 by ulcerative colitis. During the vaccination cycle, half of the patients (53%) were on stable treatment with aminosalicylates, and 32% were on biological therapy. No differences in antibody concentrations between IBD patients and HCs, nor T-cell responses, were found. Stratifying IBD patients based on the type of treatment (anti-TNFα agents vs. other treatment regimens), a decrease only in antibody titer (p = 0.008), but not in cellular response, was observed. Even after the COVID-19 vaccine booster dose, the TNFα inhibitors selectively decreased the humoral immune response compared to patients on other treatment regimens. The T-cell response was preserved in all study groups. These findings highlight the importance of evaluating T-cell immune responses following COVID-19 vaccination in a routine diagnostic setting, particularly for immunocompromised cohorts.

Anti-TNF-α induced paradoxical psoriasis in patients with ankylosing spondylitis: a systematic review.

The approval of TNF-a inhibitors (TNFi) was a breakthrough in the treatment of ankylosing spondylitis (AS). Although also effective in psoriasis, drug-related adverse events of onset of psoriasiform skin lesions - paradoxical psoriasis (PP) under TNFi have been reported. We performed an electronic data search in MEDLINE via Pubmed and Cochrane library scientific databases from inception to January 2023, following the PRISMA guidelines. We assessed the distinct characteristics and frequency of risks for PP appearance in AS patients treated with different TNFi. PP was found in 0.5-1% of TNFi-treated AS patients and the latency period was 2-11 months. The safest TNFi in terms of PP induction was certolizumab, whereas the one most commonly associated with PP was infliximab. PP is an uncommon adverse reaction to TNFi treatment in AS patients and responds well to drug withdrawal. More large data studies need to be conducted though, to shed light on PP nature and management.

Effects of Biologic Therapy on Laboratory Indicators of Cardiometabolic Diseases in Patients with Psoriasis

Psoriasis is associated with cardiometabolic and cardiovascular diseases. Biologic therapy targeting tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17 may improve not only psoriasis but also cardiometabolic diseases. We retrospectively evaluated whether biologic therapy improved various indicators of cardiometabolic disease. Between January 2010 and September 2022, 165 patients with psoriasis were treated with biologics targeting TNF-α, IL-17, or IL-23. The patients' body mass index; serum levels of HbA1c, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol, triglyceride (TG), and uric acid (UA); and systolic and diastolic blood pressures were recorded at weeks 0, 12, and 52 of the treatment. Baseline psoriasis area and severity index (week 0) positively correlated with TG and UA levels but negatively correlated with HDL-C levels, which increased at week 12 of IFX treatment compared to those at week 0. UA levels decreased at week 12 after ADA treatment compared with week 0. HDL-C levels decreased 52 weeks after IXE treatment. In patients treated with TNF-α inhibitors, HDL-C levels increased at week 12, and UA levels decreased at week 52, compared to week 0. Thus, the results at two different time points (at weeks 12 and 52) were inconsistent. However, the results still indicated that TNF-α inhibitors may improve hyperuricemia and dyslipidemia.

Brexanolone therapeutics in post-partum depression involves inhibition of systemic inflammatory pathways.

Brexanolone has rapid, long-lasting, and remarkable efficacy in the treatment of post-partum depression (PPD). We test the hypothesis that brexanolone inhibits proinflammatory modulators and macrophage activation in PPD patients, which may promote clinical recovery. PPD patients (N=18) provided blood samples before and after brexanolone infusion according to the FDA-approved protocol. Patients were unresponsive to prior treatment before brexanolone therapy. Serum was collected to determine neurosteroid levels and whole blood cell lysates were examined for inflammatory markers and invitro responses to the inflammatory activators lipopolysaccharide (LPS) and imiquimod (IMQ). Brexanolone infusion altered multiple neuroactive steroid levels (N=15-18), reduced levels of inflammatory mediators (N=11) and inhibited their response to inflammatory immune activators (N=9-11). Specifically, brexanolone infusion reduced whole blood cell tumor necrosis factor-α (TNF-α, p=0.003), and interleukin-6 (IL-6, p=0.04) and these effects were correlated with HAM-D score improvement (TNF-α, p=0.049; IL-6, p=0.02). Furthermore, brexanolone infusion prevented LPS and IMQ-induced elevation of TNF-α (LPS: p=0.02; IMQ: p=0.01), IL-1β (LPS: p=0.006; IMQ: p=0.02) and IL-6 (LPS: p=0.009; IMQ: p=0.01), indicating inhibition of toll-like receptor (TLR)4 and TLR7 responses. Finally, inhibition of TNF-α, IL-1β and IL-6 responses to both LPS and IMQ were correlated with HAM-D score improvements (p<0.05). Brexanolone actions involve inhibition of inflammatory mediator production and inhibition of inflammatory responses to TLR4 and TLR7 activators. The data suggest that inflammation plays a role in post-partum depression and that inhibition of inflammatory pathways contributes to the therapeutic efficacy of brexanolone. The Foundation of Hope, Raleigh, NC and UNC School of Medicine, Chapel Hill.

Current management of generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes of sterile pustules accompanied by inflammation and, often, systemic involvement. The inflammatory nature of GPP has potential for severe multisystem complications including high-output cardiac failure, infections, digestive system issues, and disfiguring or lethal acute flare episodes. The disease tends to have higher prevalence in females and Asians. The IL-1/IL-36 inflammatory pathway is a critical facet of GPP's pathology. Genetic mutations that are associated with GPP include modifications of Interleukin 36 Receptor Antagonist (IL36RN), Caspase Recruitment Domain Family Member 14 (CARD14), Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3), Myeloperoxidase (MPO) and Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) genes. Treatment guidelines for GPP are not well-entrenched. Currently, only one GPP-specific treatment, the interleukin-36 receptor antagonist (IL-36Ra) spesolimab, has been approved for use in the United States. Additional anti-IL-36 pathway therapies are currently being developed. Other treatment options include other biologic therapies such as IL-17 inhibitors, IL-23 inhibitors and TNFα inhibitors. Non-biologic therapeutic options include retinoids, cyclosporine and methotrexate. Treatment options differ throughout the world; most countries utilize retinoids, cyclosporine and methotrexate as first-line non-biologic options. China and United Kingdom have no GPP-specific biologic therapies approved for use, while several biologic therapies are approved for use in Japan. This review aims to serve as an update on the current global management of GPP while also including relevant aspects of disease pathogenesis, diagnosis, clinical presentation, histopathology, aetiology and epidemiology.

Infliximab induced severe depression and suicidal thoughts in patient with bipolar disorder

IntroductionInfliximab is a tumor necrosis factor-alpha (TNF-α) inhibitor commonly used in the treatment of autoimmune disorders such as rheumatoid arthritis and ankylosing spondylitis. An increased risk of opportunistic infections, malignancy, and neurodegenerative diseases have been widely documented as adverse effects of IFX therapy. Few reports exist serving the notice of new-onset psychiatric symptoms linked to IFX treatment, such as suicidal behaviors in adults and elderly patients, as well as psychosis in an adolescent. Psychiatric side effects while under IFX treatment are reported to be rare.ObjectivesHere, we present a case of a female with bipolar disorder who developed a long-standing depressive episode with suicidal thoughts after her fourth infusion of infliximab for her ankylosing spondylitisMethodsRetrospective life chart was created, including infliximab infusion.Montgomery Asberg Depression Scale was applied at time of hospitalisation and discharge.The Naranjo Adverse Drug Reaction Probability Scale was applied.ResultsA 55 year old female with ankylosing spondylitis and bipolar disorder was treated with IFX for 8 months. During this period, a total of 4 infusions were administered and AS symptoms were well responding to the treatment. Patient describes the onset of depressive symptoms such as anhedonia and insomnia after the infusion of third IFX infusion, gradually progressing to loss of function and suicidal thoughts and hospitalization in a psychiatry clinic.The patient had a history of bipolar disorder for 10 years with recurrent manic and depressive episodes, 4 hospitalisations and 1 cure of ECT. Patient was on sertraline, maprotiline and diazepam at the time of hospitalization. We started treatment with aripiprazole, quetiapine and valproate, followed for 4 weeks as an inpatient, consulted with rheumatology treatment options and neurology for demyelinating disorders, no pathology was discovered. Rheumatology suggested the continuation of IFX infusion under psychiatric control. Fifth dose of IFX infusion was administered and patient was discharged after euthymic mood was established and insomnia and suicidal thoughts were deteriorated. Upon follow up, depressive symptoms recurred and lamotrigine was added for augmentation.Image:ConclusionsAlthough there is very scarce evidence that IFX causes psychiatric symptoms, there are few clinical trials too, showing evidence that TNF-alpha inhibitors may improve depressive symptoms. While we need more information and evidence to support the ideas of TNF alpha inhibitors effects on human neuropsychology, it is of great importance for especially patients with psychiatric history to be closely watched while administering the product, at least to minimize unintended adverse events.Disclosure of InterestNone Declared