Tumor Necrosis Factor Alpha Inhibitors Research Articles

Tumor Necrosis Factor Alpha Blockade and Multiple Sclerosis: Exploring New Avenues.

Multiple sclerosis (MS) is the most common disabling disease of the central nervous system (CNS) with a progressive neurodegenerative pattern. It is characterized by demyelination of white matter in CNS and apoptosis of oligodendrocytes. Tumor necrosis factor (TNF) alpha is a major cytokine in the pathogenesis of MS. However, the failure of TNF alpha inhibitors in preclinical and clinical trials disapproved of their use in MS patients. Nevertheless, failures and misses sometimes open avenues for new hits. In the later years, it was discovered that TNF signaling is mediated via two different receptors, TNFR1 and TNFR2, both of which have paradoxical effects. TNFR1 mediates demyelination and apoptosis, while TNFR2 promotes remyelination and neuroprotection. This explained the cause of the failure of non-selective TNF alpha-blockers in MS. It also enlightened researchers that repurposing the previously formulated non-selective TNF alpha-blockers using a receptor-selective approach could lead to discovering novel biologic agents with a broader spectrum of indications and better safety profiles. This review focuses on a novel premier TNFR1 blocker, atrosab, which has been tested in animal models of MS, experimental autoimmune encephalomyelitis (EAE), where it demonstrated a reduction in symptom severity. The early promise shown by atrosab in preclinical studies has given us hope to find another revolutionary drug for MS in the future. Clinical trials, which will finally decide whether this drug can be used as a better therapeutic agent for MS or not, are still going on, but currently, there is no approved evidence regarding efficacy of these agents in treating MS.

Pustular Psoriasis: A Narrative Review of Recent Developments in Pathophysiology and Therapeutic Options.

Pustular psoriasis is an unusual form of psoriasis that frequently presents clinical challenges for dermatologists. The condition presents with pustules on an erythematous background and has two distinct subtypes: localized disease on the palms and soles, called palmoplantar pustulosis (PPP), and generalized pustular psoriasis (GPP). The involvement of the fingers, toes, and nails is defined as a separate localized variant, acrodermatitis continua of Hallopeau, and is now thought to be a subset of PPP. The rarity of pustular psoriasis frequently makes the correct diagnosis problematic. In addition, treatment is limited by a relative lack of evidence-based therapeutic options. Current management is often based on existing therapies for standard plaque psoriasis. However, there remains a need for treatments with high, sustained efficacy and a rapid onset of action in pustular psoriasis. Recent advances in understanding of the pathogenesis of pustular psoriasis have provided insights into potential therapies. Treatment of pustular psoriasis is generally determined by the extent and severity of disease, and recent years have seen an increasing use of newer agents, including biologic therapies. Current classes of biologic therapies with US Food and Drug Administration and European Medicines Agency approval for treatment of moderate-to-severe plaque psoriasis in the USA (and elsewhere) include tumor necrosis factor alpha inhibitors (adalimumab, certolizumab pegol, etanercept, infliximab), interleukin (IL)-17 inhibitors (brodalumab, ixekizumab, secukinumab), an IL-12/23 inhibitor (ustekinumab), and IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab). Recently, specific inhibitors of the IL-36 pathway have been evaluated in GPP and PPP, including spesolimab, an IL-36 receptor inhibitor which has shown promising results in GPP. The emerging drugs for pustular psoriasis offer the possibility of rapid and effective treatment with lower toxicities than existing therapies. Further research into agents acting on the IL-36 pathway and other targeted therapies has the potential to transform the future treatment of patients with pustular psoriasis. This article reviews the clinical features of PPP and GPP, and current understanding of the genetics and immunopathology of these conditions; it also provides an update on emerging treatments.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00612-x.

Membranous nephropathy complicating relapsing polychondritis: A case report

Background: Relapsing polychondritis is a rare systemic disease characterized by recurrent inflammation, and often destruction, of cartilaginous tissues. Renal manifestations are rare. Membranous nephropathy complicating relapsing polychondritis has been reported only once previously, and there is no standardized treatment for membranous nephropathy associated with relapsing polychondritis. Case presentation: A 67-year-old Caucasian man with a history of chronic renal disease presented with 9 months of progressive dyspnea on exertion and 5 months of erythema, pain, and collapse of auricular cartilage. Imaging studies confirmed active inflammation of laryngeal, auricular, and costal cartilage and he was diagnosed with relapsing polychondritis. Patient had longstanding proteinuria and renal biopsy demonstrated membranous nephropathy. Patient initially showed renal and respiratory improvement with etanercept, a tumor necrosis factor alpha inhibitor, treatment. However, subsequent disease and treatment-related complications led to a progressive overall clinical decline and patient died approximately 1 year following relapsing polychondritis diagnosis. Conclusion: Membranous nephropathy may rarely complicate relapsing polychondritis. In our case, both the cartilaginous inflammation and the renal disease improved after treatment with tumor necrosis factor alpha blockade, however complications of existing airway disease led to recurrent hospitalizations and eventually death.

BAMLANIVIMAB-INDUCED GUILLAIN-BARRÉ SYNDROME

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Guillain-Barre syndrome (GBS) is an autoimmune post-infectious neuropathy resulting in acute ascending flaccid paralysis 1. To the best of our knowledge and review of literature, this is the first reported case of GBS after receiving bamlanivimab a monoclonal antibody immunotherapy, now authorized for use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CASE PRESENTATION: A 61-year-old male presented with acute progressive ascending bilateral lower extremity weakness and fever. Previous medical history included Chronic obstructive pulmonary disease and a recent diagnosis of SARS-CoV-2 for which he received monoclonal antibody (Bamlanivimab) one week prior to admission. On admission, neurological exam was remarkable for decreased bilateral lower and upper extremity strength with poor hand grip strength. Patient was being monitored in the intensive care unit for respiratory failure using negative inspiratory force and vital capacity. Lumbar puncture results were remarkable for normal glucose (62 mg/dL), elevated protein (122.4 mg/dL) without an elevated white blood count. The patient was diagnosed with GBS and initially treated with Intravenous Immunoglobin (IVIG) for five days. However, he continued to be symptomatic and developed mild dysarthria and facial weakness. He was subsequently treated with plasmapheresis for five days. Neurological and respiratory function improved after plasmapheresis therapy. DISCUSSION: The case illustrates GBS presentation after treatment with monoclonal antibody therapy in the setting of SARS-CoV-2. Bamlanivimab is an IgG1κ monoclonal antibody that targets the spike protein of SARS-CoV-2 and prevents the attachment and entry of the virus into human cells. In mild-moderate cases, Bamlanivimab was authorized to treat mild-moderate SARS-CoV-2 in patients above 12 years old, weight more than 40 kg, and high risk of disease progression and/or hospitalization.2,3 In this case report, the patient developed GBS within a short time period after receiving Bamlanivimab. Other case studies have also reported subsequent development of GBS after treatment with monoclonal antibodies.4,5,6 Ipilimumab, an IgG1 monoclonal antibody that inhibits cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), was associated with GBS development after its use as an adjuvant therapy for patients with melanoma. 4,5 Adalimumab (a tumor necrosis factor alpha inhibitor) was also reported with GBS development when used as therapy for psoriasis and psoriatic arthritis. 6 These monoclonal antibodies have different mechanisms of action and were used in other disorders. CONCLUSIONS: This case report demonstrates that monoclonal antibodies may develop an autoimmune response. This case report is important in highlighting GBS as a potential side effect of Bamlanivimab given its potential for respiratory compromise and its current use in mild to moderate SARS-CoV-2.1,3 REFERENCE #1: Leonhard, S.E., Mandarakas, M.R., Gondim, F.A.A. et al. Diagnosis and management of Guillain–Barre syndrome in ten steps. Nat Rev Neurol 2019;15:671–683. REFERENCE #2: Chen, P., Nirula, A., Heller B. et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2021;384:229-237 REFERENCE #3: U.S. Food and Drug Administration. (2021, March 31). Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibody for Treatment of COVID-19. Retrieved from https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19 DISCLOSURES: no disclosure on file for Nia Jagroop;No relevant relationships by Visala Natarajan, source=Web Response No relevant relationships by Gladys Palaguachi, source=Web Response no disclosure on file for Benhoor Shamian;

Novel strategies for the diagnosis and treatment of scleritis

ABSTRACT Introduction Scleritis is a severe, vision-threatening ocular inflammation often associated with systemic diseases that carry high risks of morbidity. Timely diagnosis and management are crucial to prevent sequela. Areas Covered This review encompasses the etiology, pathophysiology, classification, diagnosis, and treatment of scleritis with an emphasis on novel diagnostic and treatment modalities. A review of the literature was performed using the keywords ‘scleritis,’ ‘autoimmune diseases,’ ‘non-steroidal anti-inflammatory drugs,’ ‘antimetabolite,’ ‘immunomodulatory therapy,’ ‘tumor necrosis factor alpha inhibitors,’ biologic response modifier’ and ‘optical coherence tomography.’ Expert Opinion Scleritis is mainly a clinical diagnosis. Nevertheless, multimodal imaging may be used in diagnostically challenging cases. New approaches such as anterior segment optical coherence tomography (OCT), OCT angiography (OCTA), and ultrasound biomicroscopy (UBM) may serve as more objective measures to diagnose and monitor scleritis patients. The etiology, severity, anatomical location, and associated systemic inflammatory diseases should be considered when determining scleritis treatment. Currently, first-line treatment in low grade non-necrotizing anterior scleritis is usually non-steroidal anti-inflammatory drugs (NSAIDs) and/or topical/systemic corticosteroids. In non-responsive cases, systemic immunomodulatory therapy (IMT) is recommended. Novel treatment with biologic response modifiers (BRMs) is promising in refractory scleritis. Further studies are needed to evaluate efficiency and safety of BRMs.

S1715 A Case of Collagenous Colitis Masquerading as Crohn’s Disease

Introduction: Collagenous colitis (CC) is a subtype of microscopic colitis characterized by chronic large volume watery diarrhea, few or no endoscopic abnormalities, and histopathology showing irregular subepithelial collagenous band-like deposits and epithelial lymphocytic infiltration. Colonic ulceration in CC is rare, with frequency between 1.9-3.0%. We present a patient with diffuse colonic ulceration on endoscopy, but with biopsy findings and response to treatment consistent with CC. Case Description/Methods: A 34-year-old woman with psoriatic arthritis, uveitis, and Grave’s disease was referred for colonoscopy for chronic diarrhea evaluation. She reported a one-year history of 7-10 watery, non-bloody bowel movements per day associated with abdominal cramping. She denied fever or weight loss but endorsed many years of daily non-steroidal anti-inflammatory drug (NSAID) use to manage arthritic pain. Prior work up was notable for fecal calprotectin (FC) of 226 ug/g and normal C-reactive protein of 0.3 mg/dL. Colonoscopy revealed moderate patchy erythema with tiny ulcerations throughout the colon with notable rectal sparing (Figure 1). The appearance of the ulcerations combined with the patient's history of uveitis and psoriatic arthritis suggested a diagnosis of Crohn’s colitis. However, biopsies revealed dramatic and diffuse thickening of the subepithelial collagen layer with entrapment of inflammatory cells and capillaries, and an accompanying moderate increase in intraepithelial lymphocytes. The patient was treated for CC with complete NSAID cessation and a course of Budesonide 9 mg daily. At six week follow up she reported complete resolution of diarrhea within 3 days of Budesonide initiation. Discussion: Although ulcerative CC is rare, it has a strong association with NSAID use compared to non-ulcerative CC (61% vs. 78%). Clinical remission rates with Budesonide treatment are high, anywhere from 57% to 100%. Clinical remission occurs quickly, typically in less than 7 days, as was the case with our patient. Given her comorbidities and elevated FC, the possibility of CC and inflammatory bowel disease (IBD) co-occurrence was considered, However, multiple studies have shown elevated FC levels in microscopic colitis compared to controls. Furthermore, CC is usually followed by development of IBD, or years after IBD treatment with tumor necrosis factor-alpha inhibitors. This case illustrates a rare manifestation of CC with ulceration in a clinical context otherwise consistent with Crohn’s colitis.Figure 1.: Figure 1a: Ulcerated mass in cecum as seen on initial colonoscopy. Figure 1b: Cecum on repeat colonoscopy one month later with marked improvement in ulcerations.

Effects of long-term infliximab and tocilizumab treatment on anxiety-like behavior and cognitive function in naive rats.

Circulating cytokines have been proposed to be implicated in the development of mood disorders and cognitive impairment. This study aims to examine the effect of chronic treatment with infliximab, a tumor necrosis factor-alpha (TNF-alpha) inhibitor, and tocilizumab, an antibody against interleukin-6 (IL-6) receptor on anxiety-like behavior and cognitive function. Twenty-eight male, Wistar rats were randomly allocated into negative control, vehicle, infliximab and tocilizumab groups. After 8weeks of intraperitoneal drug administration, rats performed the elevated-plus maze, the elevated-zero maze, the olfactory social memory and the passive avoidance tests. Brain sections at the level of the hippocampus, the amygdala and the prefrontal cortex were histologically examined. Finally, hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Infliximab group exhibited a significantly higher number of entries and time spent into the open arms of the mazes, showing a lower level of anxiety. In the olfactory social memory test, tocilizumab significantly increased the ratio of interaction. Both infliximab- and tocilizumab-treated animals had a significantly lower latency time in the passive avoidance test that suggests an improved memory. Histological examination revealed similar morphology and neuronal density between groups. BDNF expression levels were significantly increased in the groups receiving anti-cytokine treatment. Our findings suggest that long-term peripheral TNF-alpha and IL-6 inhibition improves anxiety and cognitive function in rats and leads to an increased BDNF expression in the brain.

Cardiovascular Risk Associated With TNF Alpha Inhibitor Use in Patients With Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and pannus formation, with subsequent joint and cartilage degradation. Treatment commonly targets inflammatory cytokines, including tumor necrosis factor (TNF) alpha, which is a potent inflammatory cytokine required for cell signaling, regulation, and apoptosis, as well as for other cellular functions including immune response. TNF alpha inhibitors have demonstrated benefits in improving RA patient outcomes in terms of immune function and symptomatology. While TNF alpha inhibitors are generally beneficial, some studies have demonstrated that TNF alpha inhibitors may increase the risk of adverse cardiovascular events. While this continues to be debated, our study investigates the role of Tumor Necrosis Factor Receptor 1 (TNFR1) and Tumor Necrosis Factor Receptor 2 (TNFR2) in cardiac tissue. TNFR1 is an apoptotic receptor and its inhibition by TNF alpha inhibitors is subsequently cardioprotective. However, TNF alpha inhibitors may be inhibiting TNFR2 receptors even more so than TNFR1 receptors. TNFR2 is primarily a cardioprotective receptor and its greater inhibition results in the cardiovascular morbidity associated with TNF alpha inhibitors.

L-carnitine protects cardiac damage by reducing oxidative stress and inflammatory response via inhibition of tumor necrosis factor-alpha and interleukin-1beta against isoproterenol-induced myocardial infarction

Brief introductionMyocardial infarction (MI) is a common manifestation of certain cardiac diseases where oxidative stress and fibrosis aggravate the condition markedly. Main objective of the studyInvestigation of L-carnitine’s cardioprotective roles and mechanism of action in a rat model of MI. MethodsTo develop a MI animal model, Isoproterenol (ISO) was administered in male Long Evans rats where animals were divided into five groups (six rats/group). The oxidative stress and antioxidant enzyme activities were determined by different biochemical tests. The real-time PCR was performed to determine the expression of TNF-α and Il-1β. Histopathological observations by hematoxylin-eosin and Masson trichrome were made to observe the tissue damage and fibrosis in heart and kidney. Significant findings from the studyThe ISO-treated rats showed increased levels of troponin I and lipid peroxidation and lower antioxidant enzyme activity in heart and kidney tissues. The levels of TNF-α and IL-1β were also increased in ISO-rats. Co-administration of L-carnitine with ISO reversed all these parameters. The elevated levels of uric acid and creatinine kinase and ALP, AST and ALT activities in ISO-rats were also significantly reduced by L-carnitine administration. L-carnitine markedly decreased the infiltration of inflammatory cells and improved the tissue architecture in heart and kidney. Control animals did not show any appreciable response upon L-carnitine administration. Relevant contribution to knowledgeThese results suggest that L-carnitine plays a defensive role against cardiac and renal damage in ISO-treated MI rat model via suppressing oxidative stress and increasing antioxidant enzyme functions through inhibition of TNF-α and IL-1β.

Adalimumab for CNS sarcoidosis: single-center experience and literature review.

Tumor necrosis factor (TNF) alpha is critical in the development of granulomas and multiple recent reports have highlighted the role of infliximab, an infused TNF alpha inhibitor, in the treatment of neurosarcoidosis. As a self-injected TNF alpha inhibitor, adalimumab has certain advantages over infused medications, including greater patient freedom and autonomy. Experience with adalimumab is not well reported in the literature. To report clinical experience with adalimumab in the treatment of central nervous system (CNS) sarcoidosis by combining observations in our center with those that have been reported in the literature. Patients were identified from the Mass General Brigham Research Patient Data Registry and in the literature by searching PubMed. Patients with CNS manifestations of sarcoidosis treated with adalimumab were included for retrospective review and analyzed for baseline characteristics, treatment indications, outcomes, and adverse effects. Adalimumab was commonly started after failure of or intolerance to infliximab and methotrexate. Of those with adequate follow-up, 5/10 ultimately improved, remission was maintained in 3/10, and 2/10 with active disease remained stable without further worsening. One patient suffered a relapse, likely multifactorial in etiology, but has remained relapse free on adalimumab for 10months subsequently. Three patients ultimately discontinued adalimumab. Preliminary evidence suggests that adalimumab may be a reasonable therapeutic option for patients with neurosarcoidosis affecting the CNS, including those with medically refractory disease.

Treatment Persistence in Patients Cycling on Subcutaneous Tumor Necrosis Factor-Alpha Inhibitors in Inflammatory Arthritis: A Retrospective Study.

Biologic treatments including subcutaneous tumor necrosis factor-alpha inhibitors (SC-TNFis) have greatly improved disease management of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) (collectively inflammatory arthritis, IA). Nevertheless, some patients discontinue their first-line treatment; for them, one option may be a subsequent line of the same treatment class (i.e., cycling). The aim of this study was to assess treatment persistence between first- and second-line therapy in Swedish IA patients cycling on SC-TNFis. Using data from the Swedish Health Data Registers, adult IA patients filling prescriptions between May 1, 2010, and October 31, 2016, for a SC-TNFi (adalimumab, etanercept, certolizumab and golimumab) were included. Treatment persistence was derived based on information from filled prescriptions and a 60-day grace period. Unadjusted and adjusted marginal Cox proportional hazards models were fitted to estimate the relative risk of discontinuation across treatment lines, using robust sandwich covariance matrix estimates to account for intrapatient dependence (i.e., multiple treatment lines per patient). The analysis was restricted to the first two lines of treatment. Of the eligible patients, 3181 were identified as cyclers. Among these, most were female (68%), and 46%, 28% and 26% were diagnosed with RA, AS and PsA, respectively. Both the unadjusted and adjusted analyses showed that the relative risk of discontinuing SC-TNFi treatment was significantly lower in second compared to first line (hazard ratio; 0.60 [0.57, 0.63] and HR; 0.59 [0.56, 0.62]). This finding was also consistent across IA indications. In this study of patients cycling on SC-TNFis in IA, persistence was greater in second- compared to first-line treatment. The finding was consistent across all IA indications. Hence, patients who discontinue their first-line treatment may still benefit from treatment with an alternative SC-TNFi as a second-line therapy in IA.

Protective role of the alpha-1-antitrypsin in intervertebral disc degeneration

BackgroundIntervertebral disc degeneration is a complex disease with high prevalence. It suggests that cell death, senescence, and extracellular matrix degradation are involved in the pathogenesis. Alpha-1 antitrypsin (AAT), a serine protease inhibitor, was previously correlated with inflammation-related diseases. However, its function on intervertebral disc degeneration remains unclear.MethodsA latex-enhanced immunoturbidimetric assay measured the serum level of AAT. Real-time polymerase chain reaction (RT-qPCR) and western blot were used to testify the expression of RNA and proteins related to cell apoptosis and the Wnt/β-catenin pathway. The animal model for intervertebral disc degeneration was built by disc puncture. The degeneration grades were analyzed by safranin o staining.ResultsWe showed that alpha-1 antitrypsin could ameliorate intervertebral disc degeneration in vitro and in vivo. We also found that the serum alpha-1 antitrypsin level in Intervertebral disc degeneration patients is negative related to the severity of intervertebral disc degeneration. Moreover, alpha-1 antitrypsin was also showed to suppress tumor necrosis factor-alpha (TNF-α) induced WNT/β-catenin signaling pathway activation in human nucleus pulposus cells.ConclusionsOur study provides evidence for AAT to serve as a potential therapeutic reagent for the treatment of intervertebral disc degeneration.

Long noncoding RNA intersectin\xa01-2 gradually declines during adalimumab treatment, and its reduction correlates with treatment efficacy in patients with ankylosing spondylitis

Previous studies show that long noncoding RNA intersectin 1-2 (lnc-ITSN1-2) promotes the inflammation process and serves as a potential biomarker in autoimmune diseases, except for ankylosing spondylitis (AS). Therefore, this study aimed to explore the correlation of baseline lnc-ITSN1-2 expression with disease risk and activity of AS, and to investigate its longitudinal change with treatment response to a tumour necrosis factor alpha (TNFα) inhibitor in patients with AS. In total, 63 patients with AS receiving 12-week adalimumab treatment were included and their baseline clinical features were collected. Lnc-ITSN1-2 expression in peripheral blood mononuclear cells (PBMC) of patients with AS was detected by reverse transcription quantitative polymerase chain reaction. Meanwhile, Assessment in Spondyloarthritis International Society (ASAS) 40 response was evaluated at week 2 (W2), W4, W8, and W12. According to the ASAS40 response status at W12, patients with AS were classified into responders and non-responders. PBMC lnc-ITSN1-2 expression was also determined in healthy controls (N = 60). Lnc-ITSN1-2 expression was elevated in patients with AS compared to controls (P < 0.001). Baseline lnc-ITSN1-2 expression was positively associated with C-reaction protein (CRP) (P = 0.021), interleukin (IL)-1β (P = 0.020), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score (P = 0.040), and Ankylosing Spondylitis Disease Activity score with C-reactive protein (ASDASCRP) (P = 0.045) in patients with AS. Furthermore, lnc-ITSN1-2 expression declined during the treatment with adalimumab (P < 0.001). Notably, this reduction was more obvious in responders than non-responders. In conclusion, declined lnc-ITSN1-2 expression during the TNFα inhibitor treatment correlates with good treatment efficacy in patients with AS, suggesting its clinical value for AS management.

Geraniol isolated from lemon grass to mitigate doxorubicin-induced cardiotoxicity through Nrf2 and NF-κB signaling

BackgroundGeraniol, a natural monoterpene, is a component of many plant essential oils. It contains many medicinal and pharmacological properties. Doxorubicin is an anticancer drug; however, its clinical usage is limited due to its cumulative and dose-dependent cardiotoxicity. This study investigates geraniol as a protective agent against doxorubicin-induced cardiotoxicity and explores possible underlying mechanisms of action. Methods: Male Sprague-Dawley rats were allocated into five groups. Groups 1 and 2 were administered saline and geraniol 200 mg/kg/day/orally, respectively, for 15 days. Group 3 was administered intraperitoneal doxorubicin (5 mg/kg/IP on the 5th, 10th and 15th days to achieve a cumulative dose of 15 mg/kg) to induce cardiotoxicity. The fourth and fifth groups were treated with either geraniol 100 mg/kg or 200 mg/kg orally and doxorubicin to equal the doxorubicin dose administered to Group 3. Results: Treatment with geraniol significantly ameliorated cardiac damage and restored serum cardiac injury marker levels in doxorubicin treated animals. Geraniol upregulated Nrf2 and HO-1 expression, elevated total antioxidant capacity, decreased the nuclear accumulation of kappa-light-chain enhancer of activated B cells (NF-κB), decreased the phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), suppressed tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-18 (IL-18) levels, and restored the levels of Bax and caspase-3 and 9 in heart tissue. Conclusion: Geraniol may function as a potential activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently improves Nrf2-dependent antioxidative signaling, diminishes apoptosis and subdues the inflammatory response. The downstream result is protection of the heart from doxorubicin-induced cardiotoxicity.

RETRACTED: Molsidomine alleviates acetic acid-induced colitis in rats by reducing oxidative stress, inflammation and apoptosis

Ulcerative colitis (UC) is a subcategory of intestinal inflammatory bowel disease characterized by up-regulation of proinflammatory cytokines and oxidative stress. The current study was designed to assess the probable protective effect of the nitric oxide (NO) donor, molsidomine, in experimental colitis model in rats. Rats were haphazardly classified into four groups: control, acetic acid, acetic acid + molsidomine (1 mg/kg) and acetic acid + molsidomine (2 mg/kg). Molsidomine (1 and 2 mg/kg/day) was administered by intra-peritoneal injection for 7 days prior to induction of UC. On the 8th day, colitis was induced by intra-rectal instillation of 2 ml of (4% v/v) acetic acid in normal saline using a pediatric plastic catheter. The rats were sacrificed 1 day following colitis induction, blood samples were obtained; colons and livers were isolated then underwent macroscopic, biochemical, histopathological and immunohistochemical examination. Pretreatment with molsidomine significantly reduced disease activity index, colon mass index, colonic macroscopic and histological damage. Besides, molsidomine significantly reduced the serum levels of alanine transaminase (ALT) (58.7 ± 8.9 & 59.7 ± 8 vs 288.75 ± 31.4 in AA group) and aspartate transaminase (AST) (196.2 ± 37.4 & 204 ± 30 vs 392.7 ± 35.6 in AA group). Moreover, molsidomine effectively decreased malondialdehyde (MDA) and total nitrate/nitrite (NOx) contents, and up regulated the enzymatic activity of superoxide dismutase (SOD) and glutathione level (GSH) in colonic and hepatic tissues. With regard to anti-inflammatory mechanisms, molsidomine suppressed tumor necrosis factor-alpha (TNF-α) (792.5 ± 16.7 & 448 ± 12.1 vs 1352.5 ± 45.8 in AA group) in colonic tissues and (701 ± 19 & 442.5 ± 22.5 vs 1501 ± 26 in AA group) in hepatic tissues as well as nuclear transcription factor kappa B (NF-kB/p65) levels (416.2 ± 4.1 & 185.5 ± 14.2 vs 659.2 ± 11.5 in AA group) in colonic tissues and (358 ± 6.2 & 163.5 ± 9.6 vs 732.5 ± 5.5 in AA group) in hepatic tissues. In addition, molsidomine significantly decreased inducible nitric oxide synthase (iNOS) levels (8.1 ± 0.1 & 4.9 ± 0.1 vs 16 ± 0.1 in AA group) in colonic tissues and (8.6 ± 0.3 & 6.1 ± 0.1 vs 17.8 ± 0.1 in AA group) in hepatic tissues, and myeloperoxidase (MPO) contents (10.5 ± 0.4 & 6.6 ± 0.3 vs 20.9 ± 0.6 in AA group) in colonic tissues and (13.1 ± 0.2 & 6.3 ± 0.06 vs 23.9 ± 1.4 in AA group) in hepatic tissues at p > 0.05. Furthermore, it suppressed apoptosis by reducing expression of Caspase 3 and Bax in colonic and hepatic tissues. Therefore, molsidomine might be a promising candidate for the treatment of UC.

Salidroside attenuates acute lung injury via inhibition of inflammatory cytokine production

Acute lung injury is a fatal condition characterized by excessive inflammation responses. Salidroside, the active constituent of Rhodiola rosea, possesses properties including anti-oxidation, anti-aging, anti-inflammatory, anti-hypoxia, and anti-cancer activities. In the present study, Salidroside attenuated acute lung injury via inhibition of inflammatory cytokine production. Rats pre-treated with Salidroside showed attenuated lipopolysaccharide (LPS)-induced pathological damage and suppressed tumor necrosis factor-alpha (TNFα) and interleukin 6 (IL-6) secretion in the lung. Furthermore, flow cytometry showed that Salidroside reduced the production of TNFα and IL-6 in NR8383 alveolar macrophages. These findings suggest that Salidroside may attenuate LPS-induced acute lung injury.

Association between nuclear factor of activated T cells C2 polymorphisms and treatment response in rheumatoid arthritis patients receiving tumor necrosis factor-alpha inhibitors.

Nuclear factor of activated T cells C2 (NFATC2) is known as a member of the transcription family and enhances tumor necrosis factor-alpha (TNF-α) synthesis in human T cells at the gene transcription level. Although NFATC2 has a potential role in rheumatoid arthritis (RA) progression and treatment, no study has investigated the association between NFATC2 gene polymorphisms and response status in RA patients receiving TNF-α inhibitors. This study aimed to examine the effects of polymorphisms in NFATC2, a TNF-α transcription factor, on response to TNF-α inhibitors. This prospective observational study was performed in two centers. Seven single nucleotide polymorphisms (SNPs) were investigated. Good responders were defined as patients with disease activity score (DAS)28 ≤3.2 after 6 months of treatment. Logistic regression analyses were used to investigate the association between genetic polymorphisms and response to the treatment. To test the model's goodness of fit, a Hosmer-Lemeshow test was performed. This study included 98 patients, among whom 46 showed favorable responses to the treatment. Patients with hypertension revealed an approximately three-fold lower response to TNF-α inhibitors compared to those without hypertension (23.5 vs. 76.5%; P = 0.049). After adjusting for covariates, C allele carriers of NFATC2 rs3787186 exhibited approximately three-fold lower rates of treatment response compared to those with TT genotype (P = 0.037). The Hosmer-Lemeshow test showed that the fitness of the multivariable analysis model was satisfactory (χ2 = 9.745; 8 degrees of freedom; P = 0.283). This study suggested an association between the C allele of rs3787186 and treatment response in RA patients receiving TNF-α inhibitors.

Wind of Change in the Treatment of Childhood-Onset Takayasu Arteritis: a Systematic Review.

We lack evidence-based data for the treatment of childhood-onset Takayasu arteritis (c-TA) since it is a rare disease in children. In this systematic literature review, we aimed to evaluate the treatment choices in c-TA patients and integrate our experience for the treatment of our patients in the recent years/in the biologic era. We reviewed 24 articles addressing treatments of 413 c-TA patients. Steroids were given to 352 patients (85.2%) as the main immunosuppressive therapy. Other immunosuppressive agents included methotrexate (37.3%), cyclophosphamide (24.5%), azathioprine (16.9%), and mycophenolate mofetil (7.9%). Besides, various biological agents were used, including tumor necrosis factor-alpha inhibitors in 70 of 107 c-TA patients (65.4%) and interleukin-6 inhibitors in 33 of them (30.8%). Biologics are increasingly used in our center as well. Even in severe patients, CYC is switched to either anti-TNF or antiIL6 once disease control is achieved. Recently, in addition to conventional immunosuppressants, biologics are increasingly used in c-TA. We have revised our treatment protocol to start with 1-3 doses of high-dose steroids and CYC, in a child with TA with types III-V involvement and high acute phase reactants; once clinical features subside and CRP normalizes, biologics should be started to replace CYC while decreasing the steroid dose.

Clinical, pathology-associated and molecular biomarkers of hidradenitis suppurativa/acne inversa

Hidradenitis suppurativa/acne inversa is ascarring disease of the intertrigines that is now intensively researched. Improved pathogenetic understanding has led to the introduction of tumor necrosis factor alpha (TNF‑α) inhibition, which represents amajor advance over traditional broad immunosuppression and antibiotic administration. In addition, awide range of newer and promising treatments is or is about to be clinically evaluated. These include various specific antibodies against cytokines and the complement system and small molecules. Successful use of the individual drugs depends on the stratification of suitable patient groups with the help of clinically relevant biomarkers. While molecular investigations have shown anumber of possible biomarkers and/or therapeutic target molecules, the detection of robust predictive biomarkers is still in its initial phase. In summary, the therapeutic options for hidradenitis suppurativa/acne inversa are improving through the introduction of new drugs, possibly in combination with surgical interventions, whereby the possibilities for predictive therapeutic decisions through the discovery of biomarkers would revolutionize the chances of therapeutic success.

Infliximab and tocilizumab reduce anxiety-like behavior, improve cognitive performance and reverse neuropathological alterations in juvenile rats with severe autoimmune arthritis

Several studies have demonstrated that rheumatic diseases, including Juvenile Idiopathic Arthritis (JIA), are associated with anxiety-like behavior and a cognitive decline. Infliximab, a Tumor Necrosis Factor-alpha (TNF-a) inhibitor, and tocilizumab, an antibody against Interleukin-6 (IL-6) receptor, are commonly used in the treatment of JIA. Here, we aimed to evaluate the effects of infliximab and tocilizumab on anxiety symptoms and cognitive function in a juvenile model of severe autoimmune arthritis. We found that both infliximab and tocilizumab improved anxiety-like behavior in the elevated-plus and elevated-zero maze tests. Tocilizumab, also, improved cognitive performance in the passive avoidance and olfactory social memory tests. Histological examination showed that anti-cytokine treatment reversed the histopathological alterations in the brain induced by arthritis. Further, infliximab and tocilizumab treatment increased Brain-Derived Neurotrophic Factor (BDNF) expression in the hippocampal and amygdaloid area of rat brain. In summary, our findings provide evidence that infliximab and tocilizumab have a beneficial effect on anxiety-like behavior and cognitive function and alleviate neuropathological alterations in a juvenile rat model of severe arthritis, suggesting that inhibition of TNF-a and IL-6 in the periphery, may be associated with a mood and memory enhancement in JIA patients.